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Developmental Genetics, or What Can Genetics and Genomics Tell Us About Evolution, Development, Stem Cells, Human Birth Defects, and Disease?( ^; _% f* ?3 h6 s! D: O
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The ability of researchers to answer experimental questions greatly depends9 Z% H7 E3 ^2 L( }( R
on the available technologies. New technologies lead to novel observations. ^. }0 G9 _( K- T
and field-changing discoveries and influence the types of questions that can( D7 ?% @2 A4 o* J+ A, F1 a) {
be asked. Today’s recently available technologies include sequencing and analyzing 3 S8 W j5 V1 \" |the genomes of human and model organisms, genome-wide expression- D0 y0 _2 E- E7 y5 P
profiling, and high-throughput genomic and genetic analyses. The information 3 W6 R+ \5 T( p! _9 bprovided by these approaches is enabling us to begin to understand the 8 m' J2 P2 q$ Q2 S" rcomplexity of many biological processes through the elucidation of gene regulatory+ G) J3 p. t/ X2 R% x' L- r
networks, signaling pathway networks, and epigenetic modifications.! o) d$ n0 ]* V0 i! X$ _
This book describes many lines of research that are being impacting by these! s" `$ I8 s4 P2 K5 Q8 y
new technologies, including developmental genetics and the related fields of8 t) S9 A$ N- A
clinical genetics, birth defects research, stem cell biology, regenerative medicine, * O9 u) n& S( E7 Q+ h) t5 ^- N D9 U2 rand evolutionary biology. 7 K3 o2 a: ~" ~) O V6 ]The field of developmental genetics, or the study of how genes influence* L# o. w9 W% p; S' C
the developmental processes of an organism, has been influenced by new technologies) f6 y, x1 Z. U1 n3 H
and by interactions with other fields of study throughout its history.4 H a* Q9 I# F+ Z/ b, [
The concept of a genetic basis of development began in “modern” times at the1 b- v- I% H- p1 }7 m/ a3 |3 p8 X
intersection of descriptive embryology and cytology. Modern histological* i/ Y- J0 Y: I
techniques were developed in the mid-19th century, largely by Wilhelm His* f! _+ v' f# c2 p$ P
so that he could study cell division in the neural tube, which enabled visualization' D _2 T1 Y. Z2 P
of the cell nucleus, chromosomes, and the discrete steps of mitosis. 1 B' q) W8 W/ \" X! l, MTheodor Boveri cleverly applied these improved microscopic techniques to 9 V7 |/ S$ R/ y' V# ?transparent marine embryos to demonstrate that each parent contributes ; \0 W+ E! _% t. ~equivalent groups of chromosomes to the zygote, and that each chromosome - l. S6 n$ v* C8 |is an independently inherited unit. Importantly, he noted that if an embryo & I* T, o+ k$ l4 ?( b" Q! |+ V$ Dcontains the incorrect number or improper combination of chromosomes, it9 [4 t& _! y$ ^( l; ^: U7 a2 v
develops abnormally. 2 z7 M4 [% U3 H" q b- JHowever, many early embryologists rejected the idea that development is * ^: d0 ]0 p$ H! Z5 g7 D4 Udriven by prepackaged heritable particles because it seemed too similar to the # [$ a2 |2 R( Sidea of “preformation”: the concept that development is driven by predetermined9 I X: n" y: y0 z( W- n
factors or “forces” (sometimes described in rather mystical terms)., u: h# [; n7 k9 S7 ]5 F
Wilhelm Roux, an advocate of studying the embryo from a mechanistic point , y; ?' K; s% b! _8 [, bof view, was a leader in the approach of manipulating the embryo with microsurgical; Z' p1 j$ y0 m" C* Z
techniques to elucidate cause and effects between component parts$ x) y4 Q+ x3 p* {$ o
(experimental embryology). By using an animal model whose embryos were/ j/ T5 O, f, Y$ R
large, developed external to the mother, could be surgically manipulated with. X* d- i0 ]6 h% D9 a
sharpened forceps and cultured in simple salt media (i.e., amphibians), he % {& C" B7 {8 i# B7 K: A. erejected the role of predetermined factors and demonstrated the importance7 a! W/ }, \5 {& W$ L4 {# M3 L+ O% S
of external (epigenetic) influences and cell–cell interactions in regulating : @, q% ~! ^8 g) odevelopmental programs. Experimental embryologists further refined their / w; L* p/ `1 `/ Cskills at dissecting small bits of tissue from the embryo, recombining them % v" j7 r( a/ g2 ?with other tissues in culture or transplanting them to ectopic regions in the , f$ p7 ~& ~! s7 H G. T( Gembryo. This work led to the invention of tissue culture by Ross Harrison, d" Q1 }+ n% a% T' R
and the discovery of tissue inductions by Hans Spemann. 7 ]3 s- S |7 ^# R; _8 \* YWhile experimental embryology was thriving, T. H. Morgan founded the5 b1 i, u' T, S- Z
field of Drosophila genetics. Also trained as an embryologist, Morgan was & M' i3 ]! m, v: X tskeptical of Boveri’s idea of heritable packets, and directed his studies towards$ w+ V5 w/ O" j1 E* W( G
understanding the principles of inheritance. For several decades, the two fields. v8 Y m! ^/ G/ {- C- M% k! r
had little impact on one another. Interestingly, however, after a few decades of; O' ^) F5 K1 A# j4 t: P" l
study of the fruit fly, Morgan’s work supported the idea of discrete intracellular _/ ?4 B# [! a' o4 f$ \1 uparticles that directed heritable traits, which he named “genes.” Nonetheless,, ^0 O; ^3 |; a# v/ e' _
the fields of experimental embryology and genetics remained fairly" V3 s) J1 A4 |& t1 U6 L
separate entities with distinct goals and points of view. Embryologists were * j1 Y: B! z& x9 w' b( S- jelucidating the interactions that are important for the development of numerous 2 R- }2 l a8 n o* w# P3 T/ ftissues and organs, whereas geneticists were focused on the fundamentals3 h2 A2 ?! V2 Y) ]# d1 J
of gene inheritance, regulation of expression, and discovering the genetic 7 {! ~4 M" o( }* c: icode. Indeed, elucidating the genetic basis of vertebrate development was+ |0 k# H7 U; N7 J; m5 v
delayed until new technologies in molecular biology and cloning were devised. 5 [8 e% B0 B/ u6 jFrom the field of bacterial and viral genetics came the techniques for cloning/ B5 V" T2 z$ q) K
eukaryotic genes and constructing vectors for controlling expression. From/ R6 Y( j' W% g3 V" \
the classical genetic studies in fly and nematode came the rationale for mutagenizing# q0 `! G {9 |4 ^: O+ [
the entire genome and screening for developmental abnormalities.) ?& D: a, m4 I3 d+ m" e
Important regulatory genes were discovered in these invertebrates, and their , b2 W- d! N% R/ b4 Acounterparts were discovered in many other animals by homology cloning * Z5 \. y# A1 [7 Kapproaches. Thus was born the modern field that we call developmental& `: [. ^0 K2 F: G4 N# ~* x
genetics. 9 z6 c0 w% D) b$ r7 [1 tAn important advance in the past decade is the demonstration that genes. C7 Y& A* m: q% M
that regulate developmental processes in invertebrate species have important 9 Z1 J2 l4 p r* g2 `developmental functions in vertebrates. The wealth of information concerning 9 J* N+ h% v [9 sthe molecular genetic processes that regulate development in various animals 5 ^0 J. g0 v" K& v! {& l- o+ y3 tdemonstrates that developmental programs and biological processes are highly 8 q0 i0 e+ L$ {$ ]$ F# p( kconserved, albeit not identical, from yeast to human. Indeed, the Human9 z/ L% t4 P1 ~' l3 s* B
Genome Project has made it possible to identify the homologues in humans0 y9 n! y! r0 @5 q
and demonstrate that many of these regulatory genes underlie human developmental0 _( t+ X- O" m+ t& y1 q4 d
disorders and aspects of adult diseases in which differentiation processes " K6 M) d! n8 w N }0 j8 rgo awry. Currently, researchers are studying the fundamentals of: j4 s4 t/ ?6 V% U
developmental processes in the appropriate animal model and screening4 ~8 H8 I! U8 S% o9 t( m
humans for mutations in the genes identified by the basic research to be likely! O$ f+ c+ G% C- J
causative candidates. Researchers are mutagenizing vertebrate animal models ' }& y. ?* z% ?& a* v/ jand screening for mutants that resemble known human syndromes. This ! k* ~9 R9 }% x y1 f" Mcross-fertilization of fields is also impacting concepts in evolutionary biology,$ Z! h3 T% G2 h1 C9 D
xii PREFACE+ n. y4 P. S) Y- u5 ]( i
leading to a better understanding of “ancestral” species via gene expression, j K$ G% Z# R& x! B8 T0 P+ h( m
profiles, and paradigms in stem cell biology in which naı¨ve cells may be directed $ Z5 N4 A. |$ s3 f; {# Dto “designer” lineages." W- A8 t! a$ U8 a+ v# g: s
Most recently, there have been significant technological advances in " \6 l1 }0 {3 [4 s1 R2 b! p$ Igenetic, genomic, and protein expression analyses that are having a major5 g% r: w* {& B% T% f
impact on experimental approaches and analytic design. The intersection of ; D2 J0 s! D/ E3 ~& b: Fdevelopmental biology with these technologies offers a new view of developmental ' b# w, j3 W/ m e3 {. }- O* A4 Bgenetics that is only beginning to be exploited. It is this new intersection : j9 U( S8 X3 N$ qat the onset of the genomic era that is the focus of this book. The book is , W% [# [3 d1 M, o0 aorganized into sections focused on different aspects of developmental genetics. - L( U8 X+ p8 u& W' _* o" YSection I discusses the impact of new genetic and genomic technologies on' l3 v9 w4 h- t: z+ C# h! R
development, stem cell biology, evolutionary biology, and understanding ' A, z4 D. m: |# z2 fhuman birth defects. Section II discusses several major events in early embryogenesis,. b* G2 w$ P6 n# ]) g9 _& ]
fate determination, and patterning, including cellular determinants R3 z% F% X# m2 v8 [6 o4 \(Boveri revisited?), gene cascades regulating embryonic axis formation, signaling 3 S8 \. A5 o4 O Hmolecules and transcription factors that regulate pattern formation, and: [" K$ w' M [+ c$ a8 h. t, j( x9 z
the induction of the primary germ layers (ectoderm, mesoderm, and endoderm).+ ?5 B. b: g9 d& `9 \. j2 b& n
Section III describes the reorganization of the embryo via different. K2 A8 u! W+ F, b% J; V
types of morphogenetic and cellular movements that result in the foundation / j/ ^4 k: \6 M2 |2 X }3 Rof organ systems, and discusses the many signaling and adhesion molecules $ P d* |8 \, t% lthat are involved in regulating these complex processes. The final three sections ! m$ l: |4 ^8 r3 T0 S5 {focus on the signaling cascades and transcriptional pathways that regulate: f, L% R5 X. ^3 ]$ N4 E
organogenesis in representative systems derived from the embryonic8 N" o+ j" c. |/ [( d% ?7 _
ectoderm, mesoderm, and endoderm. These chapters illustrate how embryonic6 y* `6 L3 w4 ^% c: Q
rudiments become organized into adult tissues, and how defects in these processes( K$ a( [ X- Q9 |( T# ]
can result in congenital defects or disease. Each chapter demonstrates 7 B% G2 B6 E7 L2 ^1 Nthe usefulness of studying model organisms and discusses how this information: {5 z. }, |8 N/ h6 ^# i
applies to normal human development and clinical disorders. Several * r/ L8 T( {: X3 A6 cchapters also discuss the utility of stem cells to repair damaged organs and: t: G! o2 `3 A) y) l
the application of developmental genetics to the manipulation of stem cells3 U/ N- x+ i5 [4 v/ a7 P
for regenerative medicine.% Q9 E2 i; }8 k3 a4 d
The goal of this book is to provide a resource for understanding the critical ' x5 ?/ p, [$ x+ Qembryonic and prenatal developmental processes that are fundamental to4 l1 J. k; D/ d
the normal development of animals, including humans. It highlights new. _5 R/ r9 z# B5 n0 A- g
technologies to be used, new questions to be answered, and the important; u& W1 I) ?* t- e- }+ [
roles that invertebrate and vertebrate animal models have had in elucidating 1 A+ G9 e- l# T( Ethe genetic basis of human development. Developmental genetics has reemerged ( b8 p) M! k8 q6 Y- I/ o( Gfrom its birth a century ago as a nexus of diverse fields that are using) P& ~8 |4 u1 s1 z
the common language of gene sequence and function. This is influencing % w ^. c ]3 iwhat questions are posed and how the answers are used. New technologies4 p2 {! }& F* @1 I( C
are making it relatively easy to study gene expression and regulation at single / t* ?- g7 x- f* O8 {- tcell, tissue, and embryonic levels. The conservation between the genomes9 r4 G4 p4 v9 B5 b% w
of species that are separated by vast evolutionary time encourages us to * J) J, O5 V$ L+ [0 A" }, {more fully utilize animal models to gain important insights into the clinical 2 F2 ?! R) F+ ? l3 }; _$ Irelevance of the animal model data. It is our hope that this book will stimulate) i" {" U6 w: \8 q: b" N0 B* |
even more cross-fertilization and interactions between evolutionary biology,: N2 B' j5 g6 p2 m+ f7 ?! u+ y" z1 e
developmental biology, stem cell biology, basic scientists, and clinical' q) B* B t1 P: n' \
scientists.) k. v7 h+ Q0 r6 F' a7 U" {
I wish to thank all of the authors for contributing such exciting and 9 y: z) ^- S& _, k% Yexcellent chapters, and Pat Gonzalez for keeping all of us on schedule. 7 s2 q3 y* O& w, l 5 \" o) I( {( T6 e% x作者: 懵懂干细胞 时间: 2010-11-30 14:45