Information

Development - Biology


Development describes the changes in an organism from its earliest beginnings through maturity.

Figure (PageIndex{1}). (CC BY-NC-SA; N. Wheat)

Fertilization

Fertilization is the initial event in development in sexual reproduction.

  • Union of male and female gametes.
  • Recombination of paternal and maternal genes.
  • Restoration of the diploid number (two sets of chromosomes).

Zygote

The diploid cell resulting from fertilization is now called a zygote.

Figure (PageIndex{2}). development in the starfish (Phylum Echinodermata). (CC BY-NC-SA; K. Wynne)

Cleavage

Cleavage– rapid cell divisions following fertilization. Very little growth occurs while the cells are dividing. Each cell called a blastomere.

Figure (PageIndex{3}). development in the starfish (Phylum Echinodermata). (CC BY-NC-SA; K. Wynne)

This video shows cleavage in a frog embryo:

Morula

Morula– the name given to the solid ball of cells that results from cleavage. First 5-7 divisions.

Figure (PageIndex{4}). development in the starfish (Phylum Echinodermata). (CC BY-NC-SA; K. Wynne)

Blastula

As divisions continue, a fluid filled cavity, the blastocoel, forms within the embryo. The resulting hollow ball of cells is now called a blastula.

Figure (PageIndex{5}). development in the starfish (Phylum Echinodermata). (CC BY-NC-SA; K. Wynne)

Gastrulation

The morphogenetic process called gastrulation rearranges the cells of a blastula into a three-layered (triploblastic) embryo, called a gastrula, that has a primitive gut (archenteron).

Figure (PageIndex{6}). development in the starfish (Phylum Echinodermata). (CC BY-NC-SA; K. Wynne)

The Blastopore

The blastopore is the first opening in the embryo – the point of invagination during gastrulation. The blastopore will eventually become either the mouth or the anus. One end of the gut-tube or the other. The space that forms during this time is the primitive gut, the archenteron.

Figure (PageIndex{7}). development in the starfish (Phylum Echinodermata). (CC BY-NC-SA; K. Wynne)

Gastrulation

The three tissue layers produced by gastrulation are called embryonic germlayers. The ectoderm forms the outer layer of the gastrula. Outer surfaces, neural tissue

The endoderm lines the embryonic digestive tract. The mesoderm partly fills the space between the endoderm and ectoderm. Muscles, reproductive system

Gastrulation – Sea Urchin

Gastrulation in a sea urchin produces an embryo with a primitive gut (archenteron) and three germ layers.

Gastrulation - Chick

Gastrulation in the chick is affected by the large amounts of yolk in the egg. Embryo essentially sits on top of large mass of yolk.

Primitive streak– a groove on the surface along the future anterior-posterior axis.

  • Functionally equivalent to blastopore lip in frog.

Gastrulation - Mammal

In mammals the blastula is called a blastocyst. Inner cell mass will become the embryo while trophoblast becomes part of the placenta.

Figure (PageIndex{8}). blastocyst. (CC BY-NC-SA; Wikipedia)

Gastrulation in mammals involves the inner cell mass and is similar to that of the chick due to the fact that mammalian ancestors and early mammals laid eggs. The large mass of yolk may be gone, but the developmental pattern remains.

Suites of Developmental Characters

Two major groups of triploblastic animals:

  • Protostomes include flatworms, annelids and molluscs.
  • Deuterostomes include echinoderms and chordates.

Protostomes & Deuterostomes

Protostomes & deuterostomes are differentiated by:

  • Spiral vs. radial cleavage
  • Mosaic vs. regulative cleavage
  • Blastopore becomes mouth vs. anus
  • Schizocoelousvs. enterocoelous coelom formation.

Spiral vs. Radial Cleavage

Spiral cleavage– occurs in most protostomes. Some ecdysozoans show radial or superficial (insects) cleavage.

Figure (PageIndex{9}). (CC BY-NC-SA; N. Wheat)

Radial cleavage– is found in most deuterostomes. Tunicates and mammals have specialized cleavage patterns.

Figure (PageIndex{10}). (CC BY-NC-SA; N. Wheat)

Mosaic vs. Regulative Development

Mosaic development– cell fate is determined by the components of the cytoplasm found in each blastomere. An isolated blastomere can’t develop. Protostomes

Regulative development– the fate of a cell depends on its interactions with neighbors, not what piece of cytoplasm it has. A blastomere isolated early in cleavage is able to from a whole individual (e.g. twins). Deuterostomes

Fate of the Blastopore

Protostome means “first mouth”. Blastopore becomes the mouth. The second opening will become the anus.

Deuterostome means “second mouth”. The blastopore becomes the anus and the mouth develops as the second opening.

Figure (PageIndex{11}). development in the starfish (Phylum Echinodermata). (CC BY-NC-SA; K. Wynne)

Coelom Formation

The coelom is a body cavity found in many triploblastic organisms that is completely surrounded by mesoderm. Not all protostomes have a true coelom. Pseudocoelomates have a body cavity between mesoderm and endoderm. Acoelomates have no body cavity at all other than the gut.

In protostomes that have a coelom, a mesodermal band of tissue forms before the coelom is formed. In the process of coelom formation called schizocoely, this mesoderm splits to form a coelom.

In enterocoely, the coelom forms as outpocketingof the gut. Typical deuterostomes have coeloms that develop by enterocoely. Vertebrates use a modified version of schizocoely.



This tutorial was funded by the Title V-STEM Grant #P031S090007.


Developmental biology

The xenobots are turning some conventional views in developmental biology upside down.

For his tireless assault on evolutionary biology and downsizing the deity to fit within science, I give Meyer second place.

Complementarity as conservative Catholics use the term, however, is more than biology.

But by and large I go over the same things for every developmental stage.

Jean Piaget, the most famous developmental psychologist of the 20th Century, highlights this in a classic study.

“In the long term, I am more worried about biology,” he told The Telegraph.

Its backbone should be the study of biology and its substance should be the threshing out of the burning questions of our day.

“Botany is that branch of biology which treats of plant life” has in it the same error.

“Biology” is not so well understood as “botany,” though it is a more general term.

It follows that biology is the foundation rather than the house, if we may use so crude a figure.

It is time to abandon the notion that biology prescribes in detail how we shall run society.


Scientific Frontiers in Developmental Toxicology and Risk Assessment (2000)

The absence of an incisive understanding of the action of toxicants on development has been in large part attributable to the absence of understanding of development itself. Until a few years ago, there was no understanding of a &ldquodevelopmental mechanism&rdquo at the molecular level although there were explanations at the cellular and tissue levels, such as &ldquogastrulation is the mechanism by which the organization of the egg is transformed into the organization of the embryo.&rdquo Recent advances in developmental biology have been substantial enough for scientists to be confident for the first time that some aspects of development in some organisms are understood at the molecular level. Protein components are identified, their functions in developmental processes are known, and the time and place in the embryo of expression of the genes encoding them are known. This knowledge greatly benefits elucidating the mechanisms of developmental toxicity.

In this chapter, the committee, in response to its charge, evaluates the state of the science for elucidating mechanisms of developmental toxicity and presents insights of developmental biology. It will show the promise of the subject in the next decade for understanding the action of developmental toxicants.

A BRIEF HISTORY OF DEVELOPMENTAL BIOLOGY

Observations of embryos and embryonic stages were made and recorded in antiquity (e.g., Aristotle, fourth century BC) and with increasing attention in recent centuries (e.g., Malphigi in the 1600s, Wolff in the 1700s, and von Baer in the early 1800s). However, it was only in the late nineteenth century that scientists pursued a detailed description of the embryonic stages of a variety of verte-

brates and invertebrates, aided by the then-recent improvements in light microscopy and in staining methods and stimulated by Darwin&rsquos proposals that the study of ontogeny (i.e., the animal&rsquos embryonic development) holds clues to phylogeny (i.e., its evolutionary origin). Among the highlights during the period of 1880-1940 were the detailed anatomical descriptions of developmental stages of embryos, including the first atlas of human embryos, reconstructed from microscopic sections, published by W. His, Sr., in 1880-1885. In vertebrate embryology, these descriptions revealed the organogenesis of the heart, kidney, limbs, central nervous system (CNS), and eyes. Developmental-fate mapping studies revealed the embryonic sites of the origin of cells of the organs and the rearrangements of groups of cells in morphogenesis. The stages of development were found to include, in reverse order, cytodifferentiation, organogenesis, morphogenesis (gastrulation and neurulation), rapid cleavage, fertilization, and gametogenesis. By the 1940s, anatomical descriptions of the embryos of related animals were integrated into coherent evolutionary schemes, taught in comparative embryology classes, revealing, for example, the modification of the gill slits of jawless fish to the jaw of jawed fish and further modification to the middle ear of mammals. Also, by this time, Haeckel&rsquos oversimplified scheme had been abandoned, namely, that ontogeny merely recapitulates phylogeny.

Experimental embryology also began in the late 1800s. In experimental studies, which mostly involved techniques of cell and tissue transplantation and removal, the central role of cytoplasmic localizations and cell-lineage-restricted developmental fates was recognized in the development of certain invertebrates by the early 1900s. In vertebrate development, the importance of inductions (also called tissue interactions) was recognized in the 1920s, following the stunning organizer transplantation experiments by Spemann and Mangold (1924) on newt embryos. By the 1950s, inductions had been found in every stage and place in the vertebrate embryo, for example, in all the kinds of organogenesis. Vertebrate development, including that of mammals, had become comprehensible as a branching succession of inductive interactions among neighboring members of an increasingly large number of different cell groups of the embryo.

Developmental mechanisms, as understood even in the 1970s, were descriptions of the movements and interactions of cells or groups of cells. They were cellular- or tissue-level mechanisms. The all-important &ldquoinducers&rdquo were materials of unknown composition released by one cell group and received by another group. Consequently, the recipient cells took a path of development different from the one that would have been taken if they were unexposed. The progression or momentum of development also was recognized: that the individual events of interactions and responses are time-critical, and that certain subsequent aspects of development never occur if one event is prevented.

Molecular mechanisms, however, were not understood at that time. Embryologists encountered the limits of the field in the 1940-1970 period, as they tried to discover the chemical nature of inducers and the responses of cells to them.

The basic information and methods of biochemistry, molecular biology, cell biology, and genetics were not yet available to analyze cell-cell signaling and transcriptional regulation in embryos. In light of discouraging results, some embryologists considered that the organizer concept was faulty and that inducers were an experimental artifact (see later discussion for recent successes in understanding inductions). Although Morgan and other early geneticists had proposed that inducers and cytoplasmic localizations elicit specific gene expression and that development was in large part a problem of ever-changing patterns of gene expression (Morgan 1934), the means were not at hand to pursue those insights. Roux, Spemann, and Harrison had outlined plausible lines of inquiry into determination and morphogenesis in the early part of the twentieth century however, the means were also not available to pursue those questions at that time.

To many scientists in the 1940-1970 period, the study of development seemed messy and intractable. Researchers turned to more informative subjects such as the new molecular genetics of bacteria and phages (viruses that infect bacteria). From those inquiries came new insights in the 1950-1965 period on the nature of the gene and the code and the processes of replication, transcription, translation, enzyme induction, and enzyme repression. For example, it was only in 1961 that Monod and Jacob described gene regulation in bacteria in terms of promoters, operators, and repressor proteins (Monod and Jacob 1961). Those authors immediately saw the relevance to animal development. All of their insights made possible the invention of techniques for gene isolation and amplification, for in vitro expression of genes, for genome analysis, and, thereafter, for the new developmental biology.

With so little molecular information about developmental processes, there was scarcely any understanding of the action of developmental toxicants. For example, Wilson (1973) in his book Environment and Birth Defects could only raise the following possibilities for connections between inductions and developmental defects:

It has long been accepted that cell interactions (induction) are an important part of normal embryogenesis, despite the fact that specific &ldquoinducer substances&rdquo have not been identified. [Failures] of normal interactions which may lead to deviations in development include, for example, lack of usual contact or proximity, as of optic vesicle with presumptive lens ectoderm or the incompetence of target tissue to be activated in spite of its usual relationship with activator tissue, as in certain mutant limb defects or the inappropriate timing of the interrelation, even though all parts are potentially competent. That the nature of cell-to-cell contacts and the manner of their adhesion are important determinants in both normal and abnormal development has been demonstrated&hellip. Insufficient or inappropriate cellular interactions usually result in arrested or deviant development in the tissue ordinarily induced or activated by the interaction.

This committee will later argue that Wilson&rsquos insight was well directed and is now ready to be pursued.

ADVANCES IN DEVELOPMENTAL BIOLOGY

In the past 15 years, developmental biology has advanced remarkably, perhaps as at no other time in the field&rsquos history. It is now known that the trillions of cells of a large animal, such as a mammal, have the same genotype, which is the same as that of the single-celled zygote (the fertilized egg) from which the animal develops. That is to say, the genetic content of somatic cells does not change during the development of most animals. The recent clonings of Dolly the lamb (Wilmut et al. 1997), the Cumulina mouse family (Wakayama et al. 1998), and a nonhuman primate (Chan et al. 2000) reaffirm the fact that a specialized cell, such as a mammary or cumulus cell, carries the genes for all other kinds of cells of the animal. The scientific advances that led to these clonings were built on earlier nuclear transplantation successes in frogs, first by Briggs and King (1952), but particularly by Gurdon (1960), which had led to similar conclusions for a nonmammalian vertebrate. Despite the same genes, the cells within the individual organism differ greatly in their appearance and functions, meaning that they have the same genotype and different phenotypes. The cell types differ greatly in the ribonucleic acids (RNAs) and proteins contained within them. They differ in which subset of genes they express from their total genomic repertoire. At least 300 cell types are recognized in humans (e.g., red blood cells, Purkinje nerve cells, and smooth or striated muscle cells). The number of cell subtypes is much larger, perhaps numbering tens of thousands, when further differences are taken into account related to the cell&rsquos stage of development and location in the body, as has been discovered in recent years. Development can be viewed as evolution&rsquos crowning example of complex gene regulation. From the single genome, thousands of different gene combinations must be expressed at specific times and places in the developing organism, and from the developing egg the information for the selective use of combinations must be generated.

A major factor in this regulation is the transfer of chemical information (i.e., signals) between cells during development. From recent research, which has built on earlier findings, the following is now realized:

Embryonic cells of arthropods and nematodes make many of their developmental decisions based on which chemical signals they receive from other cells just as vertebrate embryonic cells do. Later the embryonic cells of all these organisms will make further decisions based on other signals. The cycles of signaling and responding are repeated over and over as development progresses. With that in mind and the fact that one genotype supports hundreds or thousands of cellular phenotypes, development can be said to rely on &ldquogenotype-environment interactions,&rdquo where the local environment of each cell is generated by neighboring groups of cells. The genotype and cell&rsquos previous developmental decisions determine its options for responses to the signals currently present (Wolpert 1969).

The signaling pathways involved in this information transfer are known to be of 17 types (a few more may remain undiscovered). They are used repeatedly

at different times and places in the embryo, from the earliest stages through organogenesis and cytodifferentiation, and even in the various proliferating and renewing tissues of the juvenile and adult (see Appendix C).

The signaling pathways are highly conserved across a wide range of phyla of animals (from chordates to arthropods to roundworms), presumably because they were present and already functional in the pre-Cambrian common ancestor of those animals.

Many of the kinds of cell responses to signals also are conserved (e.g., responses of selective gene expression, secretion, cell proliferation, or cell migration). The response of developing cells to signals involves activation or repression of the expression of specific genes by transcription factors contained within genetic regulatory circuits. Signaling pathways frequently affect the activity of those factors. Many of the transcription factors and circuits are conserved across a wide range of phyla of animals.

Thus, an effective and general approach to the experimental analysis of developmental processes at all stages has been to inquire about the signaling pathways and transcriptional regulatory circuits that operate in the particular instance of development under study. Different organisms, which differ in aspects of their development, nonetheless use the same conserved signaling pathways and regulatory circuits, but in different combinations, times, and places, and have different genes as the targets of their transcriptional regulatory circuits. Processes of development, which seemed to confront scientists with infinite complexity and variety just a few years ago, now seem interpretable as composites of a small number of conserved elemental processes, namely, those of intercellular signaling, intracellular regulatory circuits, and a limited variety of targeted responses. These conclusions, which were reached by the analysis of development in animals as remote as mice, flies, and nematodes, give great validity to the use of model organisms in studying mammalian development, including that of humans, and in the future analysis of the action of developmental toxicants and in their detection.

Although the signal-response pathways are highly conserved, evolution has produced an increasing complexity of the &ldquocommunity&rdquo of pathways in vertebrates. This complexity is evident both in the increased number of closely related pathway components (diversifed protein family members) and in the increased possibilities for cross-talk among pathways. The redundant function of closely related components was made evident by existence of numerous targeted gene-knockout mutations in the mouse that produced little or no identifiable pheno-types&mdashthat is, the mice are normal or nearly normal under laboratory conditions (see Table 6-5, later in this chapter). It must be emphasized, however, that functional redundancy provides two advantages. It protects the organism by ensuring that a fundamental process can proceed even in the absence or reduced presence of a critical gene activity. On an evolutionary scale, the multiplicity of overlap-

ping functions provides a basis for generating diversity without losing essential functionality.

The Drosophila Breakthrough

The recent molecular understanding of developmental processes and components was gained from the experimental analysis of a few model organisms such as Drosophila melanogaster (the fruit fly), Caenorhabditis elegans (a free-living nematode), Danio rerio (the zebrafish), Xenopus laevis (a frog), the chick, and the mouse (see Chapter 7 for proposals about their use in the assessment of developmental toxicities). D. melanogaster and C. elegans were chosen by researchers for their amenability to genetic analysis, afforded by their small size (hence, large populations) and short life cycle (hence, many generations). Nüsslein-Volhard and Wieschaus (1980) began a systematic search for developmental mutants of Drosophila in the mid-1970s. They submitted adults to high-frequency chemical mutagenesis and then inspected large populations of offspring for mutant individuals with strong and early developmental defects (before hatching) at discrete locations and discrete stages in the embryo. They discarded mutants with weak or pleiotropic effects as ones too difficult to analyze at their start. They examined mutagenized flies until the same kinds of mutants began to appear repeatedly in their collections. The recurrence was evidence that they had obtained all the different kinds of zygotic mutants (those affected in genes transcribed after fertilization) that mutagenized flies could yield under the conditions of inspection. This procedure is called &ldquosaturation mutagenesis,&rdquo in which all the susceptible genes whose encoded products are important in development are thought to be revealed. Several laboratories, including those of Nüsslein-Volhard and Wieschaus, were also collecting maternal-effect mutants (those affected in genes transcribed in female germ cells before fertilization) and pursued this search to saturation.

The Drosophila mutants were categorized by phenotype and complementation behavior (putting two mutations together in a heterozygote to see whether they are alike or different) to establish the number of different genes whose mutations give the same phenotypic defect of development. Their categories included those embryos failing to develop the anterior or posterior end, odd or even segments, dorsal or ventral parts, mesoderm, endoderm, or nervous system. Further mutant combinations were made to establish epistasis (the interaction of different gene products, reflected in the dominance of one mutant defect over another) and to deduce plausible developmental pathways in which the actions of the encoded gene products could be related and ordered. By the late 1980s, a solid base of observations of Drosophila mutant phenotypes and gene locations had been built, and ordered pathways of function based on the mutant interactions had been proposed. This information served as the foundation for future molecular genetic analysis. The research was the first systematic and exhaustive approach to under-

standing an organism&rsquos development and to identifying components of developmental processes.

Synergy with Research Advances in Other Areas

Meanwhile, other researchers worldwide made advances in biochemistry, molecular biology, cell biology, and genetics. They learned an enormous amount about the function of proteins in replication, transcription, translation, secretion, uptake, membrane trafficking, cell motility, cell division, the cell cycle, cell adhesion, and apoptosis (programmed cell death), to mention but a few of the cellular processes. Researchers improved the methods to isolate genes, sequence them, manipulate sequences, make transcripts in vitro, detect messenger (m)RNAs in cells by in situ hybridization, translate RNAs to proteins in vitro, and make antibodies to proteins. In situ hybridization, which graphically revealed the time and place of expression of specific genes in the embryo, was to prove particularly important for connecting the new molecular analysis to the older developmental anatomy. Much of the work was initially done with single-celled organisms: bacteria, yeast, or animal cells in culture. Some insights and techniques came from the study of cancer cells in the search for oncogenes.

In the course of that work, many of the processes, protein functions, and protein sequences were found to be strongly conserved among organisms as diverse as yeast and humans or even bacteria and humans. Various proteins of different organisms, and also within the same organism, shared &ldquosequence motifs&rdquo by which the protein could be recognized as a member of a protein family with a particular function and descended from a common sequence ancestor. Newly discovered proteins could be assigned a function from just their possession of a particular motif. As more motifs were found, it will be easier to categorize newly discovered proteins. For example, receptor tyrosine kinases were recognizable by their transmembrane hydrophobic motifs and adenosine triphosphate (ATP)-binding domains. G-protein-linked receptors could be distinguished by a seven-pass (serpentine) transmembrane motif. Transcription factors could be recognized by the sequence motifs of their deoxyribnucleic acid (DNA) binding domains (e.g., zinc finger, basic helix-loop-helix, homeodomain, or leucine zipper domains). Of the recently sequenced genomes of yeast and C. elegans, for example, about 40% of the open reading frames (ORFs) are recognizable by known motifs (Chervitz et al. 1998). Function can be assigned, at least preliminarily, to the products of those genes. Plans are afoot to define the function of the missing ORFs of yeast and make the functions of all proteins assignable from sequence. At the same time, there are plans to identify a large number of protein-binding sequences in the regulatory regions of genes to be able to predict better the conditions of expression of genes. These plans are among the aims of &ldquofunctional genomics,&rdquo as described in Chapter 5. All the information on sequences, motifs, and function is stored in databases available

to researchers worldwide (e.g., the Basic Local Alignment Search Tool (BLAST) <http://www.ncbi.nlm.nih.gov/BLAST/>).

Drosophila Development at the Molecular Genetic Level

By the time the Drosophila mutants were characterized in the mid-1980s, techniques were well-suited for molecular genetic analysis of affected genes and gene products. This part of the work moved quickly, thanks to gene-cloning techniques, background information about gene sequence motifs and protein function, and databases available to researchers worldwide. The successful isolation of a gene responsible for a developmental phenotype (when the gene was mutated) could be validated by the rescue of the mutant phenotype by transformation with the wild-type gene (usually as DNA included in a P-element transposon). In situ hybridization, coupled with color stains, readily revealed the normal time and place of expression of the specific genes whose mutations had been isolated. Regarding the function of these developmental genes, many were found to encode proteins with familiar motifs, such as those for receptor tyrosine kinases or various transcription factors. In fact, a surprisingly large number turned out to be transcriptional regulators. Function could be rapidly concluded from sequence data. Other Drosophila genes encoded proteins whose specific functions were unknown, yet they were recognizable generally as secreted proteins by their signal sequences or as new transcription factors by the fact they accumulated in nuclei and could bind to DNA. In the course of this analysis, new intercellular signaling pathways were discovered, such as those involving the Decapentaplegic (DPP), Hedgehog (HH), Wingless (WG), and Notch/Delta ligands. (The whimsical names are those given by researchers to mutants based on the phenotypes.)

Hundreds of laboratories worldwide joined the work on Drosophila mutants, and the picture of early development took on a satisfying coherence and clarity, especially the steps of generation of segmentation and of the overall body organization in the anteroposterior and dorsoventral dimensions. These steps of early development are known collectively as &ldquoaxis specification.&rdquo The following is a brief summary of that picture to illustrate its completeness at the molecular level. The steps are stage-specific mechanisms of development. The mechanisms are now better understood in Drosophila than in any other organism. It is the kind of information scientists would like to have, but do not yet have, for mammalian development.

At the start of Drosophila development, the oocyte is provisioned with hundreds of maternal gene products that are uniformly distributed in the egg during oogenesis. Four gene products are spatially localized in the egg, however, and they provide the initial asymmetries on which the entire anteroposterior and dorsoventral organization of the embryo is built stepwise in development after fertilization. The four gene products include the following:

An mRNA located internally at the anterior end (encoding a transcription factor, named Bicoid).

An mRNA located internally at the posterior end (encoding an inhibitor of the translation of the mRNA for a transcription factor, named Nanos).

An external protein anchored to the egg shell at both ends of the egg (involved in the production of a ligand of a receptor tyrosine kinase in the egg-cell plasma membrane).

An external protein also anchored to the egg shell but at the prospective ventral side (involved in the production of a signal ligand of the Toll receptor in the egg-cell plasma membrane).

To exemplify the steps of use of those gene products, only one of the dimensions, the anteroposterior, will be described. The two mRNAs are initially at opposite ends of the egg. They are translated after fertilization, and the encoded proteins diffuse from the ends to form opposing gradients reaching to the middle of the egg. These proteins will act in concert to generate a gradient, high at the anterior end and low at the posterior end, of another transcription factor. The nuclear number increases rapidly in the uncleaved cytoplasm. The graded transcription factors, called members of the &ldquocoordinate class&rdquo or &ldquoegg-polarity class&rdquo of gene products, activate at least eight gap genes in nuclei along the egg&rsquos length at different positions, each position unique in terms of the local quantity of transcription factors of the coordinate class. (The terms &ldquocoordinate,&rdquo &ldquoegg polarity,&rdquo and &ldquogap&rdquo also derive from mutant phenotypes.) The encoded gap proteins, which are all transcription factors themselves, accumulate in a pattern of eight broad and partially overlapping stripes along the egg&rsquos length. The proliferating nuclei are not yet separated by cell membranes&mdashthat comes later. These proteins in turn activate at least eight pair-rule genes, all of which also encode transcription factors. Complex cis-regulatory regions of the various pair-rule genes define their expression responses to the spatially distributed gap proteins. The pair-rule proteins then activate at least 12 segment-polarity genes, some of which encode transcription factors and some of which encode secreted protein signals. The pair-rule and gap proteins together also activate eight homeobox (Hox) genes to be expressed in broad stripes, as discussed in the next section. Thus, the early steps of development involve cascades of transcription factors distributed in space according to the initial gradients of a few agents and to the expression rules contained in the complex cis-regulatory regions of genes for yet other transcription factors. These key steps are accomplished in the first 3 hours of development, mostly before cell membranes are formed and gastrulation begins, although the final elaboration of the segment-polarity and Hox genes occurs after cells form.

Once the segment-polarity genes and Hox genes are activated, they maintain their expression in cells by an auto-activating circuitry, in some cases by the encoded transcription factor activating expression of its own gene. The coordi-

nate, gap, and pair-rule proteins are then no longer needed. Their products disappear, and the genes are no longer expressed.

Similar conclusions apply to the development of the termini and the dorsoventral dimension, which also rely on initially asymmetric signals. The developmental mechanisms of the termini and dorsoventral dimension are of additional interest, because the signals bind to transmembrane receptors and activate signal transduction pathways, eventually leading to the activation of transcription factors and new gene expression. These inductions are the first to occur in the developing Drosophila egg. Approximately 100 genes and encoded gene products have been identified as necessary to establish the organization of the early gastrula. Hundreds more participate in the accomplishment of these events, but they are less well described at present. In most cases, these genes probably encode proteins required in numerous developmental processes and, hence, were not recovered under the conditions of the mutant inspections used here.

As shown in Figure 6-1A-D, a coherent scheme of early development was proposed and well supported by 1992, the first of such complexity and completeness at the molecular level for any organism.

FIGURE 6-1A Outline of anteroposterior development in Drosophila and the steps of regulated gene expression (Ingham 1989). Heavy dashed arrows indicate the activation of specific gene expression by transcription factors. Thin solid arrows indicate transcription and translation. Note that Hox genes are activated by both pair-rule and gap proteins, whereas segment-polarity genes are activated by pair-rule proteins alone. In the anteroposterior dimension, segments and HOX domains are formed. Further explanation is given in Figure 6-1B.

FIGURE 6-1B Anteroposterior development in Drosophila (Nüsslein-Volhard 1991). Figure 6-1B is shown diagrammatically here, for segment formation and HOX compartment formation. The coordinate proteins Bicoid, Nanos, and Cad are translated from mRNAs localized at the two poles of the egg during oogenesis. Translation generates gradients of proteins. Bicoid and Cad are transcription factors, whereas Nanos protein inhibits the translation of another translation factor (Hunchback) in the posterior half of the egg. The graded transcription factors activate eight gap genes, and different factor concentrations activate different gap genes. The gap proteins are also transcription factors. Each diffuses locally and inhibits other gap genes, setting up eight partially overlapping stripes of gap protein along the egg&rsquos length. The gap proteins activate eight pair-rule genes, each of which has a complex cis-regulatory region and is activated by seven combinations of gap proteins, each making seven evenly spaced stripes of protein. Thus, there are 8 × 7 or 56 stripes of pair rules along the egg&rsquos length, arranged in 7-fold repeats. The pair-rule proteins are all transcription factors. These activate eight segment-polarity genes, each of which has a complex cis-regulatory region activated by at least two combinations of pair-rule proteins, to give 14 stripes of expression each. Thus, there are 14 × 8 or 104 stripes of segment-polarity proteins. The 14-fold repeat is the basis for 14 segments of the posterior head, thorax, and abdomen. The pair-rule and gap proteins together activate Hox genes in eight domains in the posterior head, thorax, and abdomen. Cell outlines are not shown, but cells are present in the two lowest panels.

FIGURE 6-1C Dorsoventral development in Drosophila (Nüsslein-Volhard 1991). The egg shell contains Pipe protein on the future ventral side, deposited there during oogenesis. After fertilization, the egg secretes several proteins into the space between the egg shell and plasma membrane. Pipe activates one of the proteins, which then sets off others in a protease cascade, the last member of which cleaves the Spätzle protein, releasing a ligand that binds to the Toll transmembrane receptor, which is uniformly distributed over the egg surface but ligand-activated only on one side. The activated receptor, via several intracellular steps, activates the Dorsal protein, a transcription factor, which enters local nuclei and activates two genes, Twist and Snail, which also encode transcription factors. Those activate other genes for gastrulation and for mesoderm formation on the ventral side. Thus, the Pipe protein is involved in a kind of mesoderm induction. Active Dorsal protein also represses the Zen and Dpp genes on the ventral side. On the dorsal side, Dorsal protein remains inactive and the Zen and Dpp genes are expressed. Laterally, there is enough active Dorsal protein to repress Zen and Dpp but not enough to activate Twist and Snail. Here, the Sog gene is permissively expressed and not repressed, preparatory to neurogenic ectoderm formation. Thus, the dorsoventral dimension of the egg is divided into three domains of gene expression. Later, the Sog protein is secreted and diffuses to the Zen, Dpp region, inhibiting Dpp signaling and allowing the division of that region into two subregions the prospective amnioserosa and prospective dorsal ectoderm.

FIGURE 6-1D The development of termini in Drosophila (Nüsslein-Volhard 1991). The Torso-like protein is present in the egg shell at the two ends of the egg, deposited there during oogenesis. After fertilization, the egg secretes several proteins into the space between the plasma membrane and egg shell. The proteins include proteases that are locally activated at the end by the Torso-like protein and release a ligand that binds locally to the transmembrane Torso receptor, a member of the RTK signal transduction family. The activated receptor locally activates Raf and MAPK, which phosphorylate a transcription factor locally, inhibiting its repression of genes and allowing local expression of the Tailless (Tll) and Huckebein (Hkb) genes involved in formation of the endoderm, terminal ectoderm, and gut involution during gastrulation. Thus, the Torso-like protein is involved in endoderm induction.

Hox Genes and the Drosophila Connection to Vertebrate Development

Even though researchers in other areas widely appreciated the breakthroughs in Drosophila development, they questioned the relevance of the information to vertebrate development. Vertebrates, as chordates, were thought to have branched from arthropods long ago and last shared a very simple common ancestor in the pre-Cambrian era (about 540 million years ago). The two groups were thought to have evolved their segmentation and heads independently. One of the first significant similarities between vertebrate and fly development came from work on homeotic genes, now called Hox genes. As mentioned before, the Hox genes are expressed in eight broad bands or spatial compartments in the anteroposterior dimension of the body shortly after gastrulation but prior to organogenesis and cytodifferentiation. Their encoded products make each spatial compartment different from the others.

The study of the eight Hox genes of Drosophila was primarily pioneered by E. Lewis from 1940 to 1970. For his work in that area, he shared the Nobel Prize

with Nüsslein-Volhard and Wieschaus in 1995. Lewis selected Drosophila mutants that exhibited mislocated body parts (e.g., wings in place of halteres (balancing organs) and legs in place of antennae). The term &ldquohomeotic&rdquo connotes such mislocation without distortion. In the homeotic mutant, the anteroposterior dimension of the animal has fewer anatomical differences along its length. For example, the Ubx mutant has an extra mesothorax located at the normal metathorax position but lacks a metathorax. It has four wings but no halteres, whereas normal Drosophila have two wings and two halteres. When the first two Hox genes (Ubx and Antp) were isolated, their sequences were compared (McGinnis et al. 1984a,b Weiner et al. 1984), and a shared 60-base sequence was found, the homeobox. The sequence is the same in both genes except for a few bases. That sequence encodes the DNA-binding motif of the encoded proteins, which are members of a large and ancient family of transcription factors. The other six Hox genes were soon isolated from Drosophila, and those too had closely related homeobox sequences. Then the eight genes were shown to exist in a contiguous cluster (actually two subclusters in D. melanogaster but one in another arthropod, Tribolium), probably all tandemly duplicated and diverged from a few founder sequences in an ancestor of arthropods. Furthermore, the members are expressed in stripes in the anteroposterior dimension of the body, in an order identical to their gene order on the chromosome (a correspondence referred to as &ldquocolinearity&rdquo of gene order and expression).

In the mid-1980s frogs and mice were found to contain similar sequences, also arranged in contiguous gene clusters. Interestingly, their expression in mice showed the same anteroposterior colinearity as that in Drosophila. As an evolutionary explanation, the common ancestor of arthropods and chordates must have had a complex Hox cluster already functioning in its development. Vertebrates, however, differ from arthropods in having at least four multi-member clusters instead of one (Krumlauf 1994). A comparison of gene arrangements and domains of expression in Drosophila and mammalian (mouse) Hox clusters is shown in Figure 6-2.

Such genes are called selector genes because their encoded products, which are transcription factors, select which other genes will be expressed in that spatial compartment of the body. The thousands of target genes of a selector-gene product encode proteins involved in subsequent local development, including the many kinds of organogenesis of different parts of the body. Hox genes have a central role in development. Because of them, the coordinate, gap, and pair-rule proteins of early development do not have to directly activate those thousands of target genes in a region-specific way but activate only the Hox genes, whose encoded proteins then do the job of regulating sets of genes in their respective regions. Methods for the directed knockout of genes in mice were invented by the mid-1980s as a way to test gene function, and the Hox genes of mice were found to control aspects of local development in their compartments, especially in vertebrae, neural tube, and neural crest derivatives. Their selector role was similar to

FIGURE 6-2 This figure illustrates the striking similarities of gene organization and expression of Hox clusters in Drosophila and mammalian (mouse) embryos. At the top is a 10-hour Drosophila embryo showing expression zones of individual Hox genes in thoracic (T1-3) and abdominal (A1-9) segments and parts of the head (Lab, labrum Mx, maxillary Ma, mandible Int, intercalary segment). Note the colinearity of Hox gene expression sites along the anterior-posterior body axis to their 3&prime to 5&prime location along the chromosome. The greatly expanded vertebrate Hox gene family is shown in the middle. These genes are arranged in four clusters (labeled A, B, C, D), each on a separate chromosome. Having arisen by duplications early in chordate evolution, Hox genes in paralogous groups (e.g., A4, B4, C4, D4 shown enclosed in dashed boxes) are more closely related than are adjacent genes (e.g., B3 vs. B4 vs. B5). The four most 5&prime paralogous groups have no close equivalent in arthropods these are expressed in the tail and fins or limbs. Lines extending from each paralogous group to the schematic brain and cranial spinal cord show the rostral limits of expression of members on each group. Note, again, the colinearity between expression sites and relative chromosomal position of most Hox genes. The same is generally true for somites and, in the proximo-distal orientation, for limbs.

that in Drosophila (Behringer et al. 1993). However, many of the target genes of Hox proteins in mice and flies are clearly different.

The Hox clusters of Drosophila and chordates are under intense study. It is now known that genes of four mouse clusters are coordinated in an elaborate circuitry of auto- and cross-activation and repression, in which the genes near the 5&prime end of the DNA sequence tend to repress genes near the 3&prime end when both are initially expressed in same cell. Equivalent paralogs in different clusters tend to overlap in the target genes they activate and repress, but each has some unique targets, as shown by the phenotypes of single-Hox knockout mutants of the mouse. As a whole, the Hox genes operate as a complex genetic regulatory system rather than as independent members.

More recently, the Hox-like Ems and Otd genes have been discovered in Drosophila as expressed in the head in regions anterior to the expression compartments of the Hox genes. Homologs of these genes (called Emx and Otx) have been found expressed in the head of the frog and mouse anterior to the Hox gene domains of the posterior head, thorax, and trunk. This was a surprise, because evolutionary biologists had thought that the vertebrate head is unique to that group and has little in common with the head of a common ancestor of vertebrates and arthropods. However, even that complexity of body organization, like HOX compartments, must predate the branching of arthropods and chordates.

The Emergence of Caenorhabditis elegans

The free-living nematode Caenorhabditis elegans emerged as an important model system in the 1970s, as the result of pioneering work on its genetics by S. Brenner (1974). Chosen for its short life cycle (3 days) and general amenability for genetic analysis, small size (1-mm length), transparency, and simplicity (only 959 somatic cells), C. elegans quickly attracted a following among developmental biologists and geneticists. In particular, J. Sulston was primarily responsible for first describing the complete cell lineage from fertilization to adulthood (Sulston and Horvitz 1977 Sulston et al. 1983) and then spearheading the physical mapping and DNA sequencing of the genome. C. elegans recently became the first metazoan organism whose genome is completely sequenced (C.elegans Sequencing Consortium 1998). In the meantime, researchers from many laboratories isolated mutants and identified many important genes controlling development, the result being that C. elegans is now the most completely described and one of the best understood models for development (see Chapter 7). In some ways, the development of vertebrates is more similar to that of C. elegans than of Drosophila (e.g., having a cellular rather than a syncyctial early embryo), and in other ways less similar (e.g., having a highly invariant cell lineage and a fixed small number of cells, no Sonic Hedgehog signaling pathway, and few HOX genes). These two model animals complement each other usefully for research into fundamental mechanisms of metazoan development.

Conserved Developmental Processes

Researchers increasingly suspected similarities of development between fruit flies and mice and began to look systematically for homologs of Drosophila developmental genes in mice, frogs, and chicks. In the late 1980s, this was a new research approach. Its success has favored the impression that at a gross level, nematodes, flies, and mice are &ldquoall the same organism&rdquo and that what is learned about one will have relevance to the others. In a genetically tractable organism, such as Drosophila or C. elegans, a gene is isolated by using a screen for a particular kind of developmental failure, and then the role of its encoded product in development is efficiently deciphered in that organism. Homologs of &ldquodevelopmentally interesting&rdquo genes are then sought in vertebrates, such as mice or frogs, in which mutant searches are still daunting due to the comparatively small populations and slow development. The homolog&rsquos function is thereafter studied in the vertebrate, for which the Drosophila or C. elegans information is used as a guide. The mouse is attractive for such studies, because the homologous gene can be knocked out and the phenotype of the null mutant examined to learn about the function of the encoded product.

A surprising array of developmental components and processes is shared between Drosophila and vertebrates (i.e., between arthropods and chordates). In addition to the EMX, OTX, and HOX organization of the body plan, they share the compartments of the dorsoventral dimension (which are thought to be inverted in orientation in one group relative to the other) the presence and mode of organogenesis of limbs (appendages), eyes, heart, visceral mesoderm, and gut the steps of cytodifferentiation during neurogenesis and myogenesis and even segmentation. Although the anatomical structures themselves are very different between arthropods and chordates, a number of the underlying steps of development are the same. These are listed in more detail in Table 6-1. The last common ancestor of chordates and arthropods was, it seems, a pre-Cambrian animal of much greater complexity than previously realized. Divergent groups of metazoa (members of the animal kingdom) can be treated as &ldquothe same organism&rdquo in the experimental analysis of many fundamentals of development. From all of those similarities, the value of model systems for gaining an understanding of difficult basic problems in mammalian development, including that of humans, is undeniable. Humans, flies, and even roundworms are less different than widely thought just 10 years ago.

Signaling Pathways in Development

An important realization to come from the Drosophila research concerns the pervasive use of cell-cell signaling in most aspects of development, starting with the termini and dorsoventral dimension (see Figures 6-1A-D) and extending to organogenesis of many kinds. Inductive signaling was thought to be important in vertebrate development, as mentioned above, but insects and other invertebrates

TABLE 6-1 Similarities of Arthropods and Chordates

Organisms That Share Process

Hox gene complex: similar order of genes in the cluster and similar order of expression domains in the posterior head and trunk (thorax and abdomen)

Anterior head organization

Ems-Otd (Emx-Otx) selector genes: similar nesting expression domains in the anterior head

Sog-Dpp-Tolloid (Chordin-BMP2,4-xolloid): similar gene expression domains, similar protein interactions in the neural versus epidermal regions similar gene expression domains in the visceral mesoderm and heart. Was the chordate dorsoventral axis formed by inverting the axis of an arthropod ancestor?

Engrailed and HH-SHH expression domains are similar in posterior half of segment or somite Hairy gene expression in alternate segments or somites

Drosophila, amphioxus, and zebrafish

Appendage or limb patterning

Similar domains of WG-HH-DPP (WNT-SHH-BMP) signaling and expression of En, Ap (En, Lmx) selector genes

Drosophila, chick, and mouse

Similar domains of expression of Eyeless-Pax6 and Sine oculis-eye selector genes

Drosophila, mouse, and human

Note: Although the organisms of these two phyla seem very different (e.g.,insects and crustaceans versus fish and mammals), they share many developmental processes at the level of their use of combinations of signaling pathways and genetic regulatory circuits. In italics are various similar conserved genes used in the conserved processes. These similarities serve as evidence that the pre-Cambrian common ancestor of chordates and arthropods was already complex in its anteroposterior and dorsoventral organization and perhaps segmented. Many aspects of cytodifferentiation are also similar (e.g., the use of MyoD in muscle and Achaete-Scute in nerve cells).

had been assumed to develop as composites of independent lineages of cells (&ldquomosaic&rdquo development). This is not at all the case. Six signaling pathways are used repeatedly in early Drosophila development: the Hedgehog, Wingless-Int (Wnt), transforming growth factor &beta (TGF&beta), Notch, receptor tyrosine kinase (RTK), and cytokine receptor (cytoplasmic tyrosine kinase) pathways. Comparative studies soon showed that these pathways exist in vertebrates as well, and most also exist in nematodes (except the Hedgehog pathway). Four other conserved pathways in addition to those six are used heavily in later development, mainly in organogenesis, and seven others come into use in the physiological functioning of the organism&rsquos differentiated cell types. The number of known pathways has now reached 17. Each pathway is distinguished by its unique set of transduction protein intermediates. The 17 pathways are listed in Table 6-2. Details of the components and steps of the individual pathways are given in Appendix C.

As a generalization, most of the pathways involve transmembrane receptor proteins that bind ligands at the extracellular face, as diagramed in Figure 6-3. Ligands arrive in some cases by free diffusion after secretion from distant neighbor cells. Others diffuse only short distances or remain attached to the surface of the cell of origin, reaching only the contacting cells. Activated receptors of the recipient cell activate the first intracellular component of a signal transduction pathway, and this then activates a subsequent component, and so on. Some pathways are long, with 7-10 intermediates. Others have one or two. The nuclear hormone receptor pathway is the shortest, having only one step. In this case, hydrophobic ligands penetrate the cell membrane on their own and bind to a receptor protein, which also functions as a transcription factor. In the longer pathways, a change of activity is passed along a series of on-off switches, which constitutes an information relay pathway, or signal transduction pathway. Ultimately, in some pathways, a protein kinase is activated at the end of the series, and that enzyme phosphorylates numerous target proteins, which change their activity (activated or inhibited) because of the phosphate addition. The target proteins are components of various basic cell processes, such as transcription, the cell cycle, motility, or secretion. Hence, these processes are turned on or off, and the change of function constitutes the cell&rsquos response to a signal. In many other pathways, a specific transcription factor is activated at the end of the pathway, and this factor is a pathway component. In development, the most frequent target of signaling pathways is indeed transcription. The pathways used in early development tend to have transcription as the only target. That is, particular transcription factors are phosphorylated or proteolyzed as a signal transduction step of the pathway, changing their activity in activating or repressing particular genes.

The pathways are used repeatedly at different times and places of development in Drosophila, nematode, and vertebrates, as listed in Table 6-3. Drosophila null mutants are usually lethal if they lack a step in any of those pathways. Lethality is an indication of the essentiality of those signaling functions. However, in the mouse (and probably all vertebrates), a null mutant for a step of a


The scope of development

All organisms, including the very simplest, consist of two components, distinguished by a German biologist, August Weismann, at the end of the 19th century, as the “ germ plasm” and the “ soma.” The germ plasm consists of the essential elements, or genes, passed on from one generation to the next, and the soma consists of the body that may be produced as the organism develops. In more modern terms, Weismann’s germ plasm is identified with DNA ( deoxyribonucleic acid), which carries, encoded in the complex structure of its molecule, the instructions necessary for the synthesis of the other compounds of the organism and their assembly into the appropriate structures. It is this whole collection of other compounds (proteins, fats, carbohydrates, and others) and their arrangement as a metabolically functioning organism that constitutes the soma. Biological development encompasses, therefore, all the processes concerned with implementing the instructions contained in the DNA. Those instructions can only be carried out by an appropriate executive machinery, the first phase of which is provided by the cell that carries the DNA into the next generation: in animals and plants by the fertilized egg cell in viruses by the cell infected. In life histories that have more than a minimal degree of complexity, the executive machinery itself becomes modified as the genetic instructions are gradually put into operation, and new mechanisms of protein synthesis are brought into functional condition. The fundamental problem of developmental biology is to understand the interplay between the genetic instructions and the mechanisms by which those instructions are carried out.


Developmental Biology

Scott F. Gilbert 
Developmental Biology.
10th Edition. 2014. Sinauer Associates: Sunderland, MA. ISBN: (Hardcover) 978-0878939787. US $114. 719 p.

At the core of biology is the study of development. How do organisms from all modes of life grow from one single cell to a complete and functional body? How do we know to establish “right” from “left,” or know to form a certain number of fingers and toes? Why can some organisms regenerate organs, while others must do without if they are lost? What processes occur as a tadpole becomes a frog? As the author states in the preface, “Metamorphic change is in the nature of science.”

Since the first edition of this textbook was written in 1985, the field of Developmental Biology has undergone a revolutionary metamorphosis from experimental embryology to developmental genetics and now integrates anatomy and genomics and systems theory to try and provide a comprehensive understanding of the developmental transitions that occur as organisms grow. This textbook seeks to describe developmental processes from all of these perspectives and is extremely successful at doing so.

Written primarily for the undergraduate student, Gilbert’s 10th edition starts at the beginning: the cycle of life. It quickly moves on to differential gene expression, a topic that most certainly has been expanded upon since the editions of previous years. The majority of the text focuses on the ever-popular stem cell: specification and cell commitment, organogenesis, embryonic development. One thing that this text does superbly well is incorporate the developmental paradigms of numerous species, including, but not limited to, drosophila, tunicates, zebrafish, frogs, birds, and, of course, humans. The text takes classic experiments dating back to the 1700s and successfully brings them up to date with fantastic fluorescent images and high resolution microscopy techniques. The diagrams that are found on nearly every page are clear and helpful, especially as a supplement for the photos. The final section of the book is on Systems Biology, or the expansion of developmental biology to medicine, ecology, and evolution. This final section, while the shortest set of chapters, will surely be expanded upon in the upcoming years.

Overall, the text is all encompassing, but if the reader wants to learn more, the 10th edition also comes with a registration code for the DevBio online laboratory. This extensive website companion to the text contains additional information on many of the subjects of the text, as well as historical and ethical perspectives on issues in developmental biology today. For the student, the videos, technique instruction, and study questions found on the site may be incredibly helpful.


Developmental Biology Center

The DBC is a group of some 50 faculty who share an interest in the processes that create the form and function of the biological world around us. At the heart of developmental biology lies a search for the mechanisms that specify cell fates, control patterning in complex tissues, and organize collections of diverse cells into organs. Deciphering these mechanisms requires many approaches, including cell biology, genetics, molecular biology, biochemistry, and neurobiology. These areas are reflected in the interests and research efforts of our faculty.

We employ a wide range of organisms and systems, and are fortunate to occupy new facilities on both the Minneapolis and St. Paul campuses. Developmental biology examines the function and interplay of genes in the context of an intact organism, and for this reason developmental biology continues to provide key insights into the functions of genes that have a huge impact on human disease. The DBC therefore provides a forum for interaction between basic research and clinical faculty, and a place for faculty from many departments to mix and exchange ideas. There are several scientific venues organized by the DBC, including weekly research talks where members share their latest results and our annual Developmental Biology Symposium. The Symposium invites top researchers from around the world to present their work in selected areas of developmental biology research and to interact extensively with our faculty, postdocs, and students.

We invite you to peruse our web site, see the breadth and depth of our research, and participate in our activities. It is a wonderful time to be a developmental biologist and at the University of Minnesota we are working hard to realize the promise that our new understanding of development can offer society.


Major contributions

Throughout its history the department has made major discoveries, including pioneering Nobel electrophysiological experiments, which identified classes of nerve fibers leading to the understanding of pain. These studies were the forerunner to today’s field of electrophysiology. And they tie in to the revolutionary pain treatment with a new class of non-steroidal anti-inflammatory therapeutics discovered here.

Experiments elucidating the mechanism of action of penicillin and commonly used antifungal agents also were first described in the department.

Recently a recombinant human therapeutic to facilitate assisted reproduction was invented here and represents the first marketable clinical agent developed at Washington University.

These findings, in addition to major contributions in fundamental biochemistry and neurophysiology, were the hallmarks of the department.


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Developmental Biology Conferences 2021/2022/2023

Developmental Biology Conferences 2021/2022/2023 is an indexed listing of upcoming meetings, seminars, congresses, workshops, programs, continuing CME courses, trainings, summits, and weekly, annual or monthly symposiums.

Developmental Biology Conferences 2021/2022/2023 lists relevant events for national/international researchers, scientists, scholars, professionals, engineers, exhibitors, sponsors, academic, scientific and university practitioners to attend and present their research activities.

Developmental Biology Conferences 2021/2022/2023 will bring speakers from Asia, Africa, North America, South America, Antarctica, Europe, and Australia.

Developmental Biology conference listings are indexed in scientific databases like Google Scholar, Semantic Scholar, Zenedo, OpenAIRE, EBSCO, BASE, WorldCAT, Sherpa/RoMEO, Compendex, Elsevier, Scopus, Thomson Reuters (Web of Science), RCSI Library, UGC Approved Journals, ACM, CAS, ACTA, CASSI, ISI, SCI, ESCI, SCIE, Springer, Wiley, Taylor Francis, and The Science Citation Index (SCI).


Developmental Biology

The Department of Developmental Biology encompasses the clinical specialties of pediatric dentistry and orthodontics, as well as scientists focused on basic research. Members of the department teach and mentor postdoctoral fellows, orthodontics fellows, pediatric dental residents, students enrolled in the DMD program, MD and PhD candidates at Harvard Medical School, and undergraduate students at Harvard University.

Full-time clinical faculty practice dentistry in the Harvard Dental Center's Faculty Group Practice , the Department of Dentistry at Boston Children’s Hospital, and at Massachusetts General Hospital part-time clinical faculty maintain private dental practices.

Full time faculty with labs at HSDM conduct research in early embryonic development, skeletal and vascular morphogenesis, the regulation of tissue growth and repair, osteoarthritis, fibrosis and osteoporosis.

This department also includes faculty at the affiliated Forsyth Institute.


Watch the video: Evolutionary Development: Chicken Teeth - Crash Course Biology #17 (January 2022).