PDF电子书：Principles of Developmental Genetics

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7 D/ u" }9 o" [8 ]9 m% k7 uDevelopmental Genetics, or What Can Genetics and Genomics Tell Us About Evolution, Development, Stem Cells, Human Birth Defects, and Disease?3 L1 d  w) k- N

) p' u5 G" @4 A* g" m% V# ~The ability of researchers to answer experimental questions greatly depends5 W' e+ v/ z3 q$ G* W2 z
on the available technologies. New technologies lead to novel observations
# M  T8 }  U% ?! ^) a" J( x, K* hand field-changing discoveries and influence the types of questions that can- g1 t( S- H5 b) c7 m4 k3 W4 @' v
be asked. Today’s recently available technologies include sequencing and analyzing
* u6 g, ^+ V0 p9 @! \; H7 {: Sthe genomes of human and model organisms, genome-wide expression1 b, ?" G( ~; Y, z2 T  `5 _
profiling, and high-throughput genomic and genetic analyses. The information0 A3 K! t8 p9 j2 M+ \
provided by these approaches is enabling us to begin to understand the
- @: j" j' i& i- K* \# |# N  b  Fcomplexity of many biological processes through the elucidation of gene regulatory
/ e- u( b& O& T( N/ b/ u6 Dnetworks, signaling pathway networks, and epigenetic modifications.3 Q$ X) _6 Q5 c) b0 |' A
This book describes many lines of research that are being impacting by these0 ~4 s+ L6 G% \. a/ _. P
new technologies, including developmental genetics and the related fields of
. O6 ?2 r( C1 P5 Y) c0 Oclinical genetics, birth defects research, stem cell biology, regenerative medicine,
5 A6 _) g3 m/ C" m' O9 N! t6 ?7 fand evolutionary biology.
. f$ A$ }- W2 D9 a; h$ j9 w% eThe field of developmental genetics, or the study of how genes influence
' w# }( s( H/ ]the developmental processes of an organism, has been influenced by new technologies2 }) |' [5 A; ]8 q7 k0 X
and by interactions with other fields of study throughout its history.) Q/ I' Y& L  V: A$ b8 U1 A
The concept of a genetic basis of development began in “modern” times at the
/ f; |! o+ W6 `intersection of descriptive embryology and cytology. Modern histological( {  }  u# {. @6 n
techniques were developed in the mid-19th century, largely by Wilhelm His
0 _/ P; G0 e- i2 u: p0 Gso that he could study cell division in the neural tube, which enabled visualization
9 Z& [5 P! z+ a2 uof the cell nucleus, chromosomes, and the discrete steps of mitosis.5 x' r7 R4 ]" |0 g, K2 N7 P
Theodor Boveri cleverly applied these improved microscopic techniques to* t! v0 B3 u/ e, t
transparent marine embryos to demonstrate that each parent contributes
: s# {" Z( p& j8 z! nequivalent groups of chromosomes to the zygote, and that each chromosome
- b5 H' ^6 e2 d' H8 pis an independently inherited unit. Importantly, he noted that if an embryo
! P, y: k9 t" b  [) d, xcontains the incorrect number or improper combination of chromosomes, it* v# o7 T* c% K
develops abnormally.
2 G: l$ r! z  ]9 w+ X2 rHowever, many early embryologists rejected the idea that development is+ B; i, P" |* N% y6 K2 D# A
driven by prepackaged heritable particles because it seemed too similar to the9 W; n$ V8 |) Z7 Y; q0 r
idea of “preformation”: the concept that development is driven by predetermined! \2 X: E3 r3 [: o
factors or “forces” (sometimes described in rather mystical terms).' p+ b; W+ [" X. ^
Wilhelm Roux, an advocate of studying the embryo from a mechanistic point# {6 O" O9 Z, D9 T$ Y( O0 b0 p
of view, was a leader in the approach of manipulating the embryo with microsurgical! F; C; i  U' @8 Z% R
techniques to elucidate cause and effects between component parts
1 o9 S1 X7 H$ T0 ^% ^/ k9 q(experimental embryology). By using an animal model whose embryos were
. |5 k* p) K# ~/ ?+ e3 I  {large, developed external to the mother, could be surgically manipulated with. O9 Y/ ~2 [/ x* u; J
sharpened forceps and cultured in simple salt media (i.e., amphibians), he
2 o' @. A, x: ^/ N' nrejected the role of predetermined factors and demonstrated the importance- |7 F6 M" N, w9 \+ u
of external (epigenetic) influences and cell–cell interactions in regulating' K0 N( j: R' w
developmental programs. Experimental embryologists further refined their
- x3 o" _$ X7 C3 v7 J$ t, \7 iskills at dissecting small bits of tissue from the embryo, recombining them
9 C- `0 i+ q! V- f* `2 X* S* \; X3 }+ ]! Ywith other tissues in culture or transplanting them to ectopic regions in the
4 G$ A& H# D& S* H% kembryo. This work led to the invention of tissue culture by Ross Harrison/ s& v5 z& y' V8 [
and the discovery of tissue inductions by Hans Spemann.: o3 E/ Z/ B4 T  N2 u" \
While experimental embryology was thriving, T. H. Morgan founded the
4 Q3 m" Q0 h) m* L! O$ m* C( u4 X6 afield of Drosophila genetics. Also trained as an embryologist, Morgan was4 ^1 a. S$ z% `
skeptical of Boveri’s idea of heritable packets, and directed his studies towards
6 l' B4 w& [" Kunderstanding the principles of inheritance. For several decades, the two fields& h/ Y0 `8 e; W; }
had little impact on one another. Interestingly, however, after a few decades of
# Z4 v  f6 X! L" istudy of the fruit fly, Morgan’s work supported the idea of discrete intracellular: W/ L" y/ {# c; M6 R  f' @/ p- U
particles that directed heritable traits, which he named “genes.” Nonetheless,
( ?  M$ l3 P$ x; F' F' Ithe fields of experimental embryology and genetics remained fairly/ G* ^. t4 f* i# }* a6 J
separate entities with distinct goals and points of view. Embryologists were+ m8 o# c# w1 C
elucidating the interactions that are important for the development of numerous
) }' o4 N8 o0 E  r: o* ctissues and organs, whereas geneticists were focused on the fundamentals- w7 [$ [/ _7 N# m$ u
of gene inheritance, regulation of expression, and discovering the genetic! A$ s- J# w: N0 `4 H
code. Indeed, elucidating the genetic basis of vertebrate development was: Y; O: V3 P' B; `" N1 h, j; J
delayed until new technologies in molecular biology and cloning were devised.+ ]1 K! |5 c( M" ~6 M
From the field of bacterial and viral genetics came the techniques for cloning
5 e( k- u5 K) e, ~& keukaryotic genes and constructing vectors for controlling expression. From
3 k9 A" P. b, m+ x  G/ `7 Q; w9 Ithe classical genetic studies in fly and nematode came the rationale for mutagenizing; \$ G2 m% x  W* O" m
the entire genome and screening for developmental abnormalities.; y4 c( D! d- k$ M- `
Important regulatory genes were discovered in these invertebrates, and their* q' w8 V2 ]* _
counterparts were discovered in many other animals by homology cloning2 n8 d: a  H. e$ A3 ]# p8 Y) I
approaches. Thus was born the modern field that we call developmental
; r6 u6 ]" Y& n6 x9 x; O; c& Hgenetics.
8 g8 R' w+ o. Z2 T8 pAn important advance in the past decade is the demonstration that genes, k8 G( N: @% m. x* K' [
that regulate developmental processes in invertebrate species have important
; }; p: `: f/ o; Cdevelopmental functions in vertebrates. The wealth of information concerning
; @" X! ?+ T- D3 q9 U3 D! ?the molecular genetic processes that regulate development in various animals; ^2 G2 C5 I0 o' I: v4 ], s
demonstrates that developmental programs and biological processes are highly
  u/ E5 O, x% mconserved, albeit not identical, from yeast to human. Indeed, the Human
  i1 o5 i% [0 SGenome Project has made it possible to identify the homologues in humans- m  b. {* D  b4 M! I
and demonstrate that many of these regulatory genes underlie human developmental
0 Y! g3 R, d& H2 Pdisorders and aspects of adult diseases in which differentiation processes% ?" p; Z  b# ]  {0 z
go awry. Currently, researchers are studying the fundamentals of
1 A+ G% \7 }2 y1 Tdevelopmental processes in the appropriate animal model and screening+ A# f: m, G6 a0 m. d- M
humans for mutations in the genes identified by the basic research to be likely( e& ^+ p2 e) J- s! c: W7 G$ g1 m! u
causative candidates. Researchers are mutagenizing vertebrate animal models
. ]) C! x; C/ J  w" Z6 n; E' iand screening for mutants that resemble known human syndromes. This" F9 O3 }) L/ v$ t! ]3 d9 V8 O
cross-fertilization of fields is also impacting concepts in evolutionary biology,* R' r8 ~* h: r+ ~! q
xii PREFACE
+ p0 U5 A  j, ^% Yleading to a better understanding of “ancestral” species via gene expression8 C, w, J- y$ u: ]# m) c; e
profiles, and paradigms in stem cell biology in which naı¨ve cells may be directed
" D* F/ `8 g( ?8 M0 Z3 ^. Xto “designer” lineages.
0 f  Q1 C7 l* t! UMost recently, there have been significant technological advances in" p9 q6 S5 M' ?) r( u3 Q
genetic, genomic, and protein expression analyses that are having a major; \# k. V) g6 v1 X* O: [  \7 E
impact on experimental approaches and analytic design. The intersection of3 |% W0 g  m7 F4 I3 b/ S
developmental biology with these technologies offers a new view of developmental
' z- e5 B6 S* _  ?! I. Rgenetics that is only beginning to be exploited. It is this new intersection
- X; c2 o* m; I2 x2 dat the onset of the genomic era that is the focus of this book. The book is
8 K# c% d9 U0 u+ Aorganized into sections focused on different aspects of developmental genetics.
8 E' e! a5 k+ r) f# v0 d1 v: {Section I discusses the impact of new genetic and genomic technologies on1 P2 N$ j$ ^, d/ c" Y
development, stem cell biology, evolutionary biology, and understanding2 e7 @& S; q, y9 ]
human birth defects. Section II discusses several major events in early embryogenesis,- r% K' Z* Z' ~
fate determination, and patterning, including cellular determinants
9 X$ }0 {- k5 o(Boveri revisited?), gene cascades regulating embryonic axis formation, signaling5 x' R* g3 \$ y
molecules and transcription factors that regulate pattern formation, and5 z* g1 h3 r7 g3 z
the induction of the primary germ layers (ectoderm, mesoderm, and endoderm).! W6 ], h" W3 G, a5 j! w$ _+ u
Section III describes the reorganization of the embryo via different. Q' q% z6 N/ E( m
types of morphogenetic and cellular movements that result in the foundation' d9 c7 A  W% k% w
of organ systems, and discusses the many signaling and adhesion molecules
) a8 K; x5 C1 }9 L) bthat are involved in regulating these complex processes. The final three sections
5 H+ m* ]0 l" c$ U- @$ ?; Ifocus on the signaling cascades and transcriptional pathways that regulate3 _. e7 X# k. O6 r
organogenesis in representative systems derived from the embryonic
, E. ^% J( c9 Q* b4 Y9 \2 O  eectoderm, mesoderm, and endoderm. These chapters illustrate how embryonic
9 b% m$ m7 V+ @rudiments become organized into adult tissues, and how defects in these processes
& Q( g# b! y% a7 \5 lcan result in congenital defects or disease. Each chapter demonstrates4 P! f. {6 A# i! u$ {
the usefulness of studying model organisms and discusses how this information# [. t2 a! N9 @1 N8 s! m
applies to normal human development and clinical disorders. Several
* _5 R. M: u/ F3 _7 Cchapters also discuss the utility of stem cells to repair damaged organs and
" b3 ]5 M6 T- \5 l# i4 B8 ithe application of developmental genetics to the manipulation of stem cells& J# w; ~. i- }. e3 `  O! P/ [8 u) l# M
for regenerative medicine., }. ~& ]9 [1 R0 c) V
The goal of this book is to provide a resource for understanding the critical
8 c0 D  C* [4 ^$ [" v7 xembryonic and prenatal developmental processes that are fundamental to
, |- m, ~0 p+ y+ \* I+ a7 ?the normal development of animals, including humans. It highlights new
( a; L" f4 R- |0 q  J7 jtechnologies to be used, new questions to be answered, and the important" q5 L6 l3 `5 k' M2 T" ?7 j
roles that invertebrate and vertebrate animal models have had in elucidating% `+ |& y2 b4 z5 Q9 K' x3 f! Y
the genetic basis of human development. Developmental genetics has reemerged  f! _1 Y/ V, I2 ]- ?
from its birth a century ago as a nexus of diverse fields that are using% v" s5 ~: J2 V( s
the common language of gene sequence and function. This is influencing9 \( S4 A: c! P) L) }: O  c& o
what questions are posed and how the answers are used. New technologies- N. i- u) @5 N7 Z7 |
are making it relatively easy to study gene expression and regulation at single2 ?1 g/ ~/ M# P3 k7 _! |! @& q+ I7 e
cell, tissue, and embryonic levels. The conservation between the genomes. r6 e* J1 M/ U/ g. c0 D& k6 u
of species that are separated by vast evolutionary time encourages us to; Y( ^. j1 q" M* }
more fully utilize animal models to gain important insights into the clinical5 U( O7 U# Z" r- e0 I; v0 j- p
relevance of the animal model data. It is our hope that this book will stimulate
& W9 B& G; m- {! G+ Z) @even more cross-fertilization and interactions between evolutionary biology,
" i# E: ^% z0 u' V# R/ ]+ jdevelopmental biology, stem cell biology, basic scientists, and clinical
; N$ `5 a6 Q8 V; }scientists.
! I, N, B7 g- l' R6 p! ~I wish to thank all of the authors for contributing such exciting and
, q1 t! \( B  H( Hexcellent chapters, and Pat Gonzalez for keeping all of us on schedule.
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