Bronner-Fraser, M.

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Gene regulatory network underlying neural crest formation
m. bronner-fraser
Division of Biology, California Institute of Technology, Pasadena, CA, USA
The neural crest is a population of multipotent, migratory progenitor
cells that forms at the border of neural and non-neural ectoderm in
vertebrate embryos. These cells then migrate from the neural tube
along defined pathways, populate numerous sites and differentiate into
diverse cells types including melanocytes, sensory and autonomic
neurons, and mineralized matrices like bone and dentine. Data com-
piled from Xenopus, zebrafish, mouse and chick, suggest that a net-
work of interacting transcriptional regulators and downstream effector
genes confer properties like multipotency and migratory capacity to
nascent neural crest cells. These regulatory interactions can be divided
into distinct phases. The first involves inductive signals (e.g. Wnt,
BMP, FGF) that establish the neural plate border, by up-regulation of
border specifier genes like Msx1/2, Pax3/7, and Zic. These border genes
in turn up-regulate neural crest specifier genes like Slug/Snail, FoxD3
and the SoxE family. Finally, the neural crest specifiers turn on specific
downstream targets that render the neural crest migratory and multi-
potent. We are testing linkages in this hypothetical neural crest gene
regulatory network in chick and lamprey by systematically perturbing
a subset of the transcription factors involved in early neural crest
specification and examining the effect of these perturbations on likely
downstream genes in order to test the predicted interrelationships. In
addition, we are isolating cis-regulatory regions of genes in this puta-
tive neural crest regulatory network to identify neural crest enhancers,
determine additional inputs to the network and determine which
interactions are direct. The results suggest that a series of gene regu-
latory circuits are involved in the production of migratory neural crest
cells in the early vertebrate embryos and that many of these events
may be conserved to the base of vertebrates.
Characterization of the Stathmin SCG10 and its interactions with
Kinesin Binding Protein (KBP) in zebrafish
gm burzynski,* m alves, e de graaf, c hoogenraad, bjl eggen,§
a brooks, rmw hofstra & i shepherd*
*Emory University, Altanta, GA, USA; University Medical Center, Groningen,
the Netherlands; Erasmus Medical Center, Rotterdam, the Netherlands; and
§University of Groningen, Groningen, the Netherlands
SCG10 (STMN2) is believed to be neuronal-specific stathmin that is
enriched in the growth cones of developing neurons and has a role in
neurite outgrowth. In all species so far examined SCG10 is expressed
in both the CNS and PNS. Recently we have shown that SCG10
interacts with the KBP (KIAA1279) protein. Mutations in kbp have
been shown to be responsible for human Goldberg-Shprintzen
(GOSHS) syndrome. Patients with this rare autosomal recessive
disorder manifest microcephaly, mental retardation, polymicrogyria,
facial dysmorphisms and Hirschsprung disease. The precise function of
KBP in nervous system development is currently not known. To begin
to understand the function of SCG10 we have determined the temporal
and spatial expression pattern of the two zebrafish SCG10 orthologues,
SCG10a and SCG10b, by RT-PCR and in situ hybridization. RT-PCR
shows that both transcripts are maternally deposited and are detectable
from 0 hpf through 5 days – the latest age we examined. In situ
hybridization analysis reveals that the pattern of expression of these
two genes is dynamic and spatially restricted but is nearly identical for
both homologues. SCG10a and b are principally restricted to the CNS
from 24–48 hpf. From 48 hpf onwards expression of both genes
becomes restricted to the anterior CNS and cranial ganglia. This pat-
tern of SCG10 expression at 48 hpf resembles the pattern of KBP gene
expression, which is limited to the anterior CNS from 48 hpf onwards.
Subsequently, both SCG10 genes are expressed additionally in the
developing gut from 72 hpf. To investigate the in vivo function of the
zebrafish SCG10 orthologues and their interactions with KBP, we
generated morpholinos (MOs) for all three genes. Morphant embryos
have a severe phenotype at relatively low MO concentration. It is
likely that there is redundancy between the two SCG10 genes as
double SCG10 morphants have a more severe phenotype when com-
pared to single morphants. Significantly, triple morphants injected
with sub-threshold doses of SCG10 and KBP MOs display a severe
phenotype, strongly suggesting an epistatic interaction between the
products of these genes. Our data suggests that SCG10 and KBP genes
are required for proper differentiation of pharyngeal arches, migration
of ENS precursors and later differentiation stages of the cranial ganglia.
Function of the RNA binding protein HERMES in gastrointestinal
morphology and motility
p de santa barbara, c rouleau, l le guen & c notarnicola
INSERM ERI25, Muscle and Pathologies, Montpellier, France
The motility of the digestive tract is ensured by the correct coordina-
tion of the autonomous enteric nervous system (ENS) and the visceral
smooth muscle cells (SMC). The ENS originates from neural crest cells
that migrate from the dorsal region of the neural tube and colonize the
whole gut to establish its innervation. The SMCs derive from the
splanchnopleural mesoderm that will form the undifferentiated vis-
ceral mesenchyme before their final differentiation. Motility disorders
in infants comprise a wide group of heterogeneous diseases. Hirsch-
sprung disease (HSCR) is a particular case due to an absence of the ENS
along certain lengths of the bowel. The SMC differentiation is also
often affected in patients with congenital gut malformations and
motility disorders such as Chronic Intestinal Pseudoobstruction (CIP).
However, few have investigated the status of SMC in physiopatho-
logical conditions. Our aim was to investigate the molecular mecha-
nisms that control the differentiation of the visceral mesenchyme into
SMCs in vertebrates. In order to identify these candidate pathways, we
developed and analyzed the gene expression profiles of undifferentiated
and differentiated avian stomach by microarray. We identified one new
candidate HERMES, a RNA binding protein and examined the function
of this factor during the development and the differentiation of the
SMC structure by performing exhaustive in vivo and in primary SMC/
ENS culture positive and negative approaches. We found that HERMES
control different aspects of the SMC differentiation and deregulation of
its expression and function alter the development of both SMC and
ENS systems. In addition, we analyzed the expression of homologous
HERMES gene in human physiopathological conditions. All these data
demonstrate the necessity of correct coordination between the
development/differentiation of the SMC and ENS and the importance
to focus on both motility effectors.
Development of the mucosal plexus of the human enteric nervous
system
m metzger,* as wallace,* kh schaefer, aj burns* & n thapar*
*UCL Institute of Child Health, London, UK; and Department of Biotechnology,
University of Applied Sciences, Kaiserslautern, Germany
Introduction: Knowledge regarding the structure and development of
the enteric nervous system (ENS) is crucial for the understanding of
gut function and its disorders. It is widely accepted that the ENS is
composed of two major plexus (myenteric and submucosal plexus)
arranged as concentric rings in the bowel wall. There is, however,
accumulating evidence from both animal studies, and our recent work
in humans, that nerve cells also reside within the post-natal intestinal
mucosa (mucosal plexus). The aim of this study was to examine the
development-dependent formation of an intrinsic mucosal plexus of
Neurogastroenterol Motil (2009)
 2009 Blackwell Publishing Ltd i


Gene regulatory network underlying neural crest formation

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Gene regulatory network underlying neural crest formation

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