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Developmental Genetics, or What Can Genetics and Genomics Tell Us About Evolution, Development, Stem Cells, Human Birth Defects, and Disease?% Z) N7 g$ m/ f' I5 L
% ~8 g. \' l7 j0 h; r+ S
The ability of researchers to answer experimental questions greatly depends
on the available technologies. New technologies lead to novel observations0 H. B# ?& ^" `' l
and field-changing discoveries and influence the types of questions that can) G# z2 @# u1 i1 X* d! d
be asked. Today’s recently available technologies include sequencing and analyzing
the genomes of human and model organisms, genome-wide expression5 Y* v. {% W: A$ i7 a  X$ ]  D5 N1 z
profiling, and high-throughput genomic and genetic analyses. The information
provided by these approaches is enabling us to begin to understand the) O( G: a( a) {% `6 q8 D
complexity of many biological processes through the elucidation of gene regulatory
networks, signaling pathway networks, and epigenetic modifications.. t" G, b7 Q: i" z7 E5 [3 m
This book describes many lines of research that are being impacting by these5 q  C8 N3 l9 e2 ?- l4 D; Y7 x6 B
new technologies, including developmental genetics and the related fields of
clinical genetics, birth defects research, stem cell biology, regenerative medicine,
and evolutionary biology.& e5 i& U8 u0 s: U' @3 B
The field of developmental genetics, or the study of how genes influence
the developmental processes of an organism, has been influenced by new technologies
and by interactions with other fields of study throughout its history.- Q1 n4 x6 x$ O( S6 p
The concept of a genetic basis of development began in “modern” times at the
intersection of descriptive embryology and cytology. Modern histological
techniques were developed in the mid-19th century, largely by Wilhelm His: _8 G4 s( R, Q4 ?2 e
so that he could study cell division in the neural tube, which enabled visualization
of the cell nucleus, chromosomes, and the discrete steps of mitosis.
Theodor Boveri cleverly applied these improved microscopic techniques to
transparent marine embryos to demonstrate that each parent contributes' f  h2 k$ Y3 T: z/ S
equivalent groups of chromosomes to the zygote, and that each chromosome* y- `" P3 m: M- z# L6 \
is an independently inherited unit. Importantly, he noted that if an embryo
contains the incorrect number or improper combination of chromosomes, it
develops abnormally.
However, many early embryologists rejected the idea that development is/ d, C3 t7 U) s6 B) C- I- |
driven by prepackaged heritable particles because it seemed too similar to the) [! j# Y& E( F  S8 x: {) f
idea of “preformation”: the concept that development is driven by predetermined
factors or “forces” (sometimes described in rather mystical terms).
Wilhelm Roux, an advocate of studying the embryo from a mechanistic point
of view, was a leader in the approach of manipulating the embryo with microsurgical, Z/ ]; W( E- Y- @8 w  j4 |0 o5 b
techniques to elucidate cause and effects between component parts) a; ]- L; R( _. v4 Q& |+ r" n; S
(experimental embryology). By using an animal model whose embryos were9 q/ O* S5 }% g& y# |8 P, k# H: T
large, developed external to the mother, could be surgically manipulated with& [4 x& `% k" t0 _( ^+ D
sharpened forceps and cultured in simple salt media (i.e., amphibians), he0 g2 ~3 |1 A/ W0 ?5 u$ z0 K4 a) n
rejected the role of predetermined factors and demonstrated the importance
of external (epigenetic) influences and cell–cell interactions in regulating
developmental programs. Experimental embryologists further refined their, k' r7 d3 l" G& \! _
skills at dissecting small bits of tissue from the embryo, recombining them
with other tissues in culture or transplanting them to ectopic regions in the
embryo. This work led to the invention of tissue culture by Ross Harrison% U; x4 D+ q/ C2 @
and the discovery of tissue inductions by Hans Spemann.
While experimental embryology was thriving, T. H. Morgan founded the6 n4 S  C3 L* y" @: ~4 S. E
field of Drosophila genetics. Also trained as an embryologist, Morgan was7 A: L* I' _9 E; C
skeptical of Boveri’s idea of heritable packets, and directed his studies towards
understanding the principles of inheritance. For several decades, the two fields
had little impact on one another. Interestingly, however, after a few decades of2 i8 m2 F! \0 q3 y! v0 R
study of the fruit fly, Morgan’s work supported the idea of discrete intracellular
particles that directed heritable traits, which he named “genes.” Nonetheless,1 ]  ^. O7 \" P0 X9 Z! u
the fields of experimental embryology and genetics remained fairly# u- K) }" `9 b. M  y6 q
separate entities with distinct goals and points of view. Embryologists were
elucidating the interactions that are important for the development of numerous
tissues and organs, whereas geneticists were focused on the fundamentals" r' ?3 f% n" z& M& k5 V7 [0 X
of gene inheritance, regulation of expression, and discovering the genetic
code. Indeed, elucidating the genetic basis of vertebrate development was
delayed until new technologies in molecular biology and cloning were devised.
From the field of bacterial and viral genetics came the techniques for cloning  y' S8 t1 ^) L6 {
eukaryotic genes and constructing vectors for controlling expression. From8 ^9 g: Y; W3 l7 ~2 z
the classical genetic studies in fly and nematode came the rationale for mutagenizing6 A7 U; A1 L/ ?5 q
the entire genome and screening for developmental abnormalities.
Important regulatory genes were discovered in these invertebrates, and their1 B/ u. O  c2 a6 o
counterparts were discovered in many other animals by homology cloning) @) m+ O- R5 g: a4 D
approaches. Thus was born the modern field that we call developmental9 ?  }% t' P# K% B% i- J! b
genetics.! T. \8 I4 M/ `6 _9 m
An important advance in the past decade is the demonstration that genes
that regulate developmental processes in invertebrate species have important
developmental functions in vertebrates. The wealth of information concerning) L% Z7 g7 f1 q
the molecular genetic processes that regulate development in various animals* T* g9 z) S$ ~$ D! K
demonstrates that developmental programs and biological processes are highly: m  V! m& q: ]) C" M
conserved, albeit not identical, from yeast to human. Indeed, the Human
Genome Project has made it possible to identify the homologues in humans2 B. k7 R# J7 S, i# N
and demonstrate that many of these regulatory genes underlie human developmental; g! T- t! Y3 n6 D. v, ^
disorders and aspects of adult diseases in which differentiation processes
go awry. Currently, researchers are studying the fundamentals of
developmental processes in the appropriate animal model and screening4 w- g: B9 L. V4 A
humans for mutations in the genes identified by the basic research to be likely
causative candidates. Researchers are mutagenizing vertebrate animal models( E- J, ]$ h, u: v9 m2 Z
and screening for mutants that resemble known human syndromes. This4 S+ d! Y: {) L
cross-fertilization of fields is also impacting concepts in evolutionary biology,2 y) [, Y) C: a0 h
xii PREFACE" L1 \$ f6 B, ^2 }# N' b! r, ~, ]
leading to a better understanding of “ancestral” species via gene expression
profiles, and paradigms in stem cell biology in which naı¨ve cells may be directed
to “designer” lineages." A, y( W1 {" g) e
Most recently, there have been significant technological advances in5 y$ ~' K" ^# b* y/ t) \5 ?6 p& d
genetic, genomic, and protein expression analyses that are having a major! ]/ Z$ Z0 c% H; W: }+ z, i
impact on experimental approaches and analytic design. The intersection of! H: S  K9 u- d" s1 ^9 K% ]4 U
developmental biology with these technologies offers a new view of developmental
genetics that is only beginning to be exploited. It is this new intersection3 Y$ K9 k& T  c" M) j) T
at the onset of the genomic era that is the focus of this book. The book is6 x7 m/ L3 r0 ?) M% ~
organized into sections focused on different aspects of developmental genetics.! H$ y7 p/ y3 I  S! o
Section I discusses the impact of new genetic and genomic technologies on" P( d7 u$ m* S, J7 Q3 l
development, stem cell biology, evolutionary biology, and understanding
human birth defects. Section II discusses several major events in early embryogenesis,# V; v+ S  j* \+ e
fate determination, and patterning, including cellular determinants
(Boveri revisited?), gene cascades regulating embryonic axis formation, signaling* L, ?& ^  D4 a2 v; O
molecules and transcription factors that regulate pattern formation, and# P( {* e  r4 ]& m' `; X/ F
the induction of the primary germ layers (ectoderm, mesoderm, and endoderm).8 x" {) |  B! \, O
Section III describes the reorganization of the embryo via different
types of morphogenetic and cellular movements that result in the foundation' t# E% \9 f) q' d7 P0 L
of organ systems, and discusses the many signaling and adhesion molecules0 U* q( ?: W' g5 H. ^
that are involved in regulating these complex processes. The final three sections' ~- I' N! c$ Q4 L* `7 K- z( y% A
focus on the signaling cascades and transcriptional pathways that regulate
organogenesis in representative systems derived from the embryonic+ a  {* i! N" _3 z
ectoderm, mesoderm, and endoderm. These chapters illustrate how embryonic9 t  c* w6 q' R3 k( M3 t8 Q
rudiments become organized into adult tissues, and how defects in these processes
can result in congenital defects or disease. Each chapter demonstrates
the usefulness of studying model organisms and discusses how this information1 X: J- [3 R. D/ u/ w
applies to normal human development and clinical disorders. Several6 H9 }' v* u: {1 Y! n0 b9 x& w
chapters also discuss the utility of stem cells to repair damaged organs and
the application of developmental genetics to the manipulation of stem cells
for regenerative medicine.) Q0 ~0 S8 d3 E& S; o# C
The goal of this book is to provide a resource for understanding the critical) Q# H: y( P! M6 E
embryonic and prenatal developmental processes that are fundamental to: A' }3 F9 W0 x9 M
the normal development of animals, including humans. It highlights new% a$ }6 @: @0 e/ |# a7 L# H9 A
technologies to be used, new questions to be answered, and the important' `$ n0 m1 @, ^; y  u& ]' U$ ~
roles that invertebrate and vertebrate animal models have had in elucidating' j: j6 D5 i. I; B% S
the genetic basis of human development. Developmental genetics has reemerged
from its birth a century ago as a nexus of diverse fields that are using
the common language of gene sequence and function. This is influencing2 ~; q! d8 O2 F7 b
what questions are posed and how the answers are used. New technologies; b9 l1 T  }3 Q1 N" r( c3 J
are making it relatively easy to study gene expression and regulation at single
cell, tissue, and embryonic levels. The conservation between the genomes+ W+ R, _+ Y& W' ?2 }
of species that are separated by vast evolutionary time encourages us to% e1 b: Y+ e) d0 j: r7 b& @
more fully utilize animal models to gain important insights into the clinical
relevance of the animal model data. It is our hope that this book will stimulate# O8 Z2 A" f0 e
even more cross-fertilization and interactions between evolutionary biology,
developmental biology, stem cell biology, basic scientists, and clinical
scientists.4 u' W1 {6 a, _
I wish to thank all of the authors for contributing such exciting and8 Q6 ~% c: l" s2 H& V& S
excellent chapters, and Pat Gonzalez for keeping all of us on schedule.+ I3 U' x- [' q  `
& g0 T$ C0 b  b

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