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TitlePrinciples of Developmental Genetics
Author
LanguageEnglish
File Size16.5 MB
Total Pages1094
Table of Contents
                            CoverPage
	FrontMatter
	TitlePage
	CopyRight
	Contents
		8-18
		19-31
		32-42
		43-INDEX
	Preface
PART ONE: THE IMPACT OF GENETIC AND GENOMIC TOOLS ON DEVELOPMENTAL BIOLOGY
	1 UNTANGLING THE GORDIANKNOT
	2 FINDING GENE EXPRESSION CHANGES USING MICROARRAY TECHNOLOGY
	3 CHEMICAL AND FUNCTIONAL GENOMIC APPROACHES TO STUDY STEM CELL BIOLOGY AND REGENERATION
	4 ASSESSING NEURAL STEM CELL PROPERTIES USING LARGE-SCALE GENOMIC ANALYSIS
	5 EPIGENETIC INFLUENCES ON GENE EXPRESSION PATHWAYS
	6 NEW INSIGHTS INTO VERTEBRATE ORIGINS
	7 UNDERSTANDING HUMAN BIRTH DEFECTS THROUGH MODEL ORGANISM STUDIES
PART TWO: EARLY EMBRYOLOGY, FATE DETERMINATION, AND PATTERNING
	8 GERM LINE DETERMINANTS ANDOOGENESIS
	9 PATTERNING THE ANTERIOR–POSTERIOR AXIS DURING DROSOPHILA EMBRYOGENESIS
	10 ANTERIOR–POSTERIOR PATTERNING IN MAMMALS
	11 SIGNALING CASCADES, GRADIENTS, AND GENENETWORKS IN DORSAL/VENTRALPATTERNING
	12 EARLY DEVELOPMENT OFEPIDERMIS AND NEURAL TISSUE
	13 FORMATION OF THE EMBRYONIC MESODERM
	14 ENDODERM
	15 NOTCH SIGNALING
	16 MULTIPLE ROLES OF T-BOX GENES
PART THREE: MORPHOGENETIC AN DCELL MOVEMENTS
	17 GASTRULATION IN VERTEBRATES
	18 REGULATION OF TISSUE SEPARATION IN THE AMPHIBIAN EMBRYO
	19 ROLE OF THE BASEMENT MEMBRANE IN CELL MIGRATION
	20 EPITHELIAL MORPHOGENESIS
	21 BRANCHING MORPHOGENESIS OF MAMMALIAN EPITHELIA
	22 THE ROLES OF EPHRIN–EPHIN MORPHOGENESIS
PART FOUR: ECTODERMAL ORGANS
	23 NEURAL CELL FATE DETERMINATION
	24 PATHFINDING AND PATTERNING OF AXONAL CONNECTIONS
	25 RETINAL DEVELOPMENT
	26 NEURAL CREST DETERMINATION
	27 DETERMINATION OF PREPLACODAL ECTODERM AND SENSORY PLACODES
	28 MOLECULAR GENETICS OF TOOTH DEVELOPMENT
	29 THE INNER EAR
	30 CRANIOFACIAL FORMATION AND CONGENITAL DEFECTS
PART FIVE: MESODERMAL ORGANS
	31 INDUCTION OF THE CARDIAC LINEAGE
	32 HEART PATTERNING AND CONGENITAL DEFECTS
	33 BLOOD VESSEL FORMATION
	34 BLOOD INDUCTION AND EMBRYONIC FORMATION
	35 TOPICS IN VERTEBRATE KIDNEY FORMATION
	36 DEVELOPMENT OF THE GENITAL SYSTEM
	37 DIAPHRAGMATIC EMBRYOGENESIS AND HUMAN CONGENITAL DIAPHRAGMATIC DEFECTS
	38 FORMATION OF VERTEBRATE LIMBS
	39 SKELETAL DEVELOPMENT
PART SIX: ENDODERMAL ORGANS
	40 PATTERNING THE EMBRYONIC ENDODERM INTO PRESUMPTIVE ORGAN DOMAINS
	41 DEVELOPMENTAL GENETICSOF THE PULMONARY SYSTEM
	42 PANCREAS DEVELOPMENTAND STEM CELLS
	43 EARLY LIVER DEVELOPMENT AND HEPATIC PROGENITOR CELLS
	44 INTESTINAL STEM CELLS IN PHYSIOLOGIC REGENERATION AND DISEASE
INDEX
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Document Text Contents
Page 2

PRINCIPLES OF DEVELOPMENTAL
GENETICS

Page 547

CAs reaching the floor plate in a mutant mouse lacking Smoothened (Smo), a
canonical signaling mediator of Shh (Charron et al., 2003).

B. Crossing the Floor Plate

After CAs arrive at the ventral midline, they must then successfully traverse
the floor plate to reach the contralateral side of the spinal cord. It has been
shown in the developing chick spinal cord that the CAMs belonging to the
immunoglobulin (Ig) superfamily, Nr-CAM and axonin-1, are required for
passage across the floor plate. Nr-CAM is localized to floor plate cells, whereas
axonin-1 is expressed on CAs. In experiments perturbing Nr-CAM or axonin-
1 in ovo using either function-blocking antibodies or RNAi, there was a
marked decrease in the number of axons that were able to cross the floor plate
(Stoeckli and Landmesser, 1995; Pekarik et al., 2003). In a separate but
related set of studies, CAs were unable to enter floor-plate explants when
function-blocking antibodies against Nr-CAM/axonin-1 were added to the
cultures, thereby supporting the idea that Nr-CAM relieves the inhibition that
CAs may perceive from floor-plate cells as they decussate (Stoeckli et al.,
1997).

Another family of guidance cues involved in midline crossing in both ver-
tebrates and invertebrates includes the Slit/Robo family. Slit, which is a large
ECM protein, was first shown to act as a midline-associated repellent based
on the phenotype observed in the Slit mutant in flies. In these mutants, CAs
projected within the ventral midline as a single longitudinal fascicle rather
than forming their usual ladder-like configuration in the ventral nerve cord
(Rothberg et al., 1990). Interestingly, it appears that the repulsive functional
role of Slit at the midline has been evolutionarily conserved from flies to
higher vertebrates (Brose et al., 1999). Recently, it was shown that CAs in
Slit1–3 triple knockout mice stall at the ventral midline and even occasionally
recross the floor plate. Similar midline defects were also observed in the chick
when reagents interfering with Slit/Robo binding were applied in ovo. Robo,
which is the receptor for Slit, is expressed selectively on longitudinal axons in
flies, and the loss of Robo results in multiple recrossing events at the ventral
midline of the nerve cord (Seeger et al., 1993).

The interpretation of this phenotype and its relationship to the Slit mutant
phenotype was not immediately clear. It was not until the discovery of comm
that the relationship between Slit and Robo was uncovered. In wild-type flies,
comm is expressed in midline glia and on CAs only as they are decussating. In
the comm fly mutant, a complete absence of commissures was observed in the
ventral nerve cord, which gave rise to its name, commissureless (Tear et al.,
1996). The interplay between Robo, Slit, and Comm required to regulate mid-
line crossing in flies was later shown to depend on both the spatial and tem-
poral precision of gene/protein expression. Through various mutant
analyses, it was established that comm is responsible for regulating the seg-
ment-specific expression pattern of Robo, and it does so by transferring Robo
into endosomes before and during midline crossing. After CAs have decussated,
Comm presents Robo on the surface of the growth cone in a cell-autonomous
manner through an as yet unidentified mechanism (Keleman et al., 2005). In
summary, the strict regulation of Robo expression via comm ensures that
CAs are insensitive to midline-associated Slit until after decussating, thereby
facilitating midline crossing in flies.

532 PATHFINDING AND PATTERNING OF AXONAL CONNECTIONS

Page 548

In the mouse, Rig-1 (Robo3) homozygous mutants phenocopy the comm
mutant, although they are molecularly distinct cues. Rig-1 protein has been
shown to be selectively expressed on precrossing CAs in the mouse and chick
(Sabatier et al., 2004), and, in Rig-1 homozygous mice, there is a complete
absence of commissures at the ventral midline at all anterior–posterior levels
of the CNS (Marillat et al., 2004). Although the mechanism through which
this occurs is still not entirely clear, in vitro evidence suggests that Rig-1 neg-
atively modulates Slit sensitivity. It was proposed that, in the absence of Rig-1,
CAs are unable to overcome the repulsion of midline-associated Slit and, as a
result, never cross the floor plate in Rig-1 homozygous mice. Recently, floor-
plate–associated ephrin-B3 and its cognate receptors were shown to regulate
the frequency of decussation of a specific commissural axon subtype in the
mouse, potentially conferring another level of regulation to guidance mole-
cules (Kadison et al., 2006b).

C. Leaving the Midline

After CAs cross through the floor plate, they must then leave the midline to
navigate toward their next choice point. For CAs to do this, they must first
lose their responsiveness to floor-plate–derived chemoattractants. This is pre-
cisely what has been shown to occur for decussated CAs, at least in the hind-
brain. CAs that have previously crossed through a floor plate were shown to
be insensitive to an ectopically positioned floor plate or to netrin-expressing
cells in vitro (Shirasaki et al., 1998). The potential mechanism underlying this
loss of netrin attraction was delineated in a series of elegant experiments
involving the Xenopus turning assay. At early stages of commissural axon
growth, isolated Xenopus spinal axons were exposed to either netrin or Slit
proteins. In this scenario, the axons were insensitive to Slit but turned toward
the source of netrin, thereby reflecting their selective responsiveness to this
attractant. At a later stage, however, the profile of responsivity drastically
changed: the spinal axons were now insensitive to netrin but repelled by Slit.
When younger spinal axons were exposed to both Slit and netrin concurrently,
they failed to elicit any response, leading the authors to investigate the mech-
anism underlying this apparent silencing of netrin attraction. Through a series
of biochemical assays and elegant chimera studies, they showed that netrin
silencing is the result of a direct interaction between the cytoplasmic domains
of Deleted in Colorectal Cancer and Robo (Stein and Tessier-Lavigne, 2001).

Along with this loss of attraction to midline-derived chemoattractants,
CAs have also been shown to gain responsiveness to midline-derived repel-
lents in vitro. An in vitro assay system with two separate configurations of
spinal cord explants was used: one configuration consisted of a half spinal
cord with a floor plate attached, and the other contained dorsal spinal cord
tissue. This approach was used to assay the response of precrossing (dorsal
spinal cord) and postcrossing (floor-plate–attached) CAs to various guidance
cues. Of the molecules assayed, Semaphorin (Sema) 3B, Sema 3F, and Slit2
were the only cues capable of inhibiting the growth of postcrossing (but not
precrossing) CAs in vitro (Zou et al., 2000). The authors proposed that these
repellent guidance cues were instructive for expelling CAs out of the vicinity
of the ventral midline and into longitudinal tracts. Defects consistent with
this role were observed in mice lacking Neuropilin-2, a receptor expressed

AXON PATHFINDING AT THE MIDLINE 533

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FIGURE 41.2

FIGURE 42.1

FIGURE 42.2

Page 1094

FIGURE 42.4 FIGURE 43.1

FIGURE 44.3

FIGURE 44.4

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