Abstracts - Society for Developmental Biology

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the mutant neural plate fails to become pseudostratified. The data suggest that Pten acts through stabilization of
microtubules to control morphogenesis of the cranial neural plate.
Program/Abstract # 110
Cdon mutation and fetal ethanol exposure synergize to produce midline signaling defects and holoprosencephaly
spectrum disorders in mice
Hong, Mingi; Krauss, Robert, Mount Sinai School of Medicine, New York, United States
Holoprosencephaly (HPE) is a remarkably common congenital anomaly characterized by failure to define the midline of
the forebrain and midface. HPE is associated with heterozygous mutations in Sonic hedgehog (SHH) pathway components,
but clinical presentation is extremely variable, and many mutation carriers are unaffected. It has been proposed that these
observations are best explained by a multiple-hit model, in which the penetrance and expressivity of an HPE mutation is
enhanced by a second mutation or the presence of cooperating, but otherwise silent, modifier genes. Non-genetic risk
factors are also implicated in HPE, and gene-environment interactions may provide an alternative multiple-hit model to
purely genetic multiple-hit models; however, there is little evidence for this contention.We report here a mouse model in
which there is dramatic synergy between mutation of a bona fide HPE gene (Cdon, which encodes a SHH co-receptor) and
a suspected HPE teratogen, ethanol. Loss of Cdon and in utero ethanol exposure in 129S6 mice give little or no phenotype
individually, but together produce defects in early midline patterning, inhibition of SHH signaling in the developing
forebrain and a broad spectrum of HPE phenotypes. Our findings argue that ethanol is indeed a risk factor for HPE, but
genetically predisposed individuals, such as those with SHH pathway mutations, may be particularly susceptible.
Furthermore, gene-environment interactions are likely to be important in the multifactorial etiology of HPE.
Program/Abstract # 111
FGF8 regulates multiple levels of neurogenesis in the zebrafish, from neural progenitor maintenance to
differentiation
Dean, Benjamin, Vanderbilt University, Nashville, United States
The habenular nuclei are part of an evolutionarily conserved conduction system in the dorsal diencephalon of the
vertebrate brain. The habenular nuclei are sites of pathogenesis and therapeutic intervention in addiction and depression.
There is no clear understanding of how these crucial brain structures develop. During CNS development, fibroblast growth
factors (FGFs) direct myriad developmental programs including the proliferation, migration and differentiation of neurons.
FGF8 has been implicated in early habenular development. Murine hypomorphic mutants of fgf8 fail to specify dorsal
diencephalic neurons including the habenular nuclei, due to altered anteroposterior (A/P) and dorsoventral (D/V)
patterning (Martinez-Ferre et al., 2009). By contrast, we have found that an fgf8 null mutation in zebrafish does not alter
A/P or D/V patterning in the dorsal diencephalon. Rather, zebrafish fgf8 mutants generate a reduced population of cells in
the vicinity of the habenular nuclei, and most of these cells fail to differentiate. We have shown that this phenotype is in
part due to reduced proliferation and increased cell death. However, it remains unclear what aspect of proliferation is
perturbed, how fgf8 impacts differentiation and which FGF receptors and pathways mediate these programs. We will use
the zebrafish fgf8 mutant to study how this brain region generates the appropriate number of neurons and how habenular
precursor cells undergo the transition from undifferentiated precursor cells into mature neurons. Towards this goal, we will
take advantage of the amenability of zebrafish embryos to transgenic overexpression, in vivo time lapse imaging and small
molecule inhibition of signaling pathways.
Program/Abstract # 112
miR-153 regulates SNAP-25, synaptic transmission and neuronal development
Wei, Chunyao, Vanderbilt University, United States; Thatcher, Elizabeth (Worcester, United States); Olena, Abigail;
Carter, Bruce; Broadie, Kendal; Patton, James (Nashville, United States)
SNAP-25 is a core component of the trimeric SNARE complex mediating vesicle exocytosis during membrane addition for
neuronal growth, neuropeptide/growth factor secretion, and neurotransmitter release during synaptic transmission. Here,
we report a novel microRNA mechanism of SNAP-25 regulation controlling neuronal development, neurosecretion,
synaptic activity, and movement in zebrafish. Loss of miR-153 causes dramatic overexpression of SNAP-25 in neurons
and consequent hyperactive movement in zebrafish embryos. Conversely, overexpression of miR-153 causes severe
SNAP-25 down regulation resulting in near complete paralysis, mimicking the effects of treatment with Botulinum
neurotoxin. Underlying the movement defects, perturbation of miR-153 function causes dramatic developmental changes
in motorneuron patterning and branching and miR-153-dependent changes in synaptic activity at the neuromuscular
junction are consistent with the observed movement defects. These results indicate that the precise control of SNAP-25
expression by miR-153 is critically important for proper neuronal growth patterning as well as neurotransmission.