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miR-34a modulates neural progenitor cell differentiation

miR-34a modulates neural progenitor cell differentiation

ABSTRACTS / Developmental Biology 319 (2008) 529–538 535 Program/Abstract # 232 Molecular networks controlling the specification of sensory organ pro...

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ABSTRACTS / Developmental Biology 319 (2008) 529–538

535

Program/Abstract # 232 Molecular networks controlling the specification of sensory organ progenitors Andrea Streit, Nicolas Christophorou, Laura Lleras Department of Craniofacial Development, King's College London, London, UK

Program/Abstract # 234 Hedgehog signaling regulates mammalian sensory cell formation and auditory function Elizabeth Carroll Driver, Matthew W. Kelley Section on Developmental Neuroscience, NIDCD, NIH, Bethesda, Maryland, USA

Vertebrate sensory placodes contribute to the paired sense organs and sensory ganglia of the head. Placode progenitors are set aside at early neurula stages, when they occupy a common field, the pre-placodal region defined by the expression of members of the Six and Eya gene families. Here, we show that Six1 and Eya2 repress neural and neural crest fates, while promoting pre-placodal gene expression. However, they are neither sufficient to induce mature otic, lens or olfactory placodes in naive ectoderm nor able to make non-placode cells competent to respond to placode inducing signals. These observations suggest that additional factors are required to specify placode precursors. We have designed a differential screen to identify such factors and present novel candidates with potential roles in the determination of placode progenitors.

Auditory function depends on the proper development of a specialized sensory epithelium within the inner ear. Within that epithelium, the formation of an appropriate number of mechanosensory hair cells and the location of those cells is critical for normal auditory perception. However, the factors that regulate the formation of the sensory epithelium remain poorly understood. Truncating mutations in the transcription factor GLI3, a downstream effector of the Hedgehog (HH) pathway, lead to a partial loss of HH signaling and cause Pallister–Hall syndrome (PHS). We have previously reported that some PHS individuals exhibit hearing loss, and that cochleae from a mouse model of PHS (Gli3Δ699) have a variably penetrant phenotype, including an increase in the size of the sensory epithelium and the development of large ectopic sensory patches in Kölliker's organ. Inhibition of HH signaling in vitro results in an increase in the size of the prosensory domain, a precursor population that gives rise to the sensory epithelium. In contrast, treatment with Sonic Hedgehog (Shh) inhibits prosensory formation. Conditional deletions of Shh or Patched also cause cochlear phenotypes consistent with an expansion or reduction of prosensory fates, respectively. Notch signaling is an inducer of prosensory fate; we demonstrate that HH signaling within the cochlea regulates expression of the Notch ligand Jagged1 and that the effects of HH are dependent on activation of Notch. These results suggest that HH signaling plays a key role in the specification, size, and location of the prosensory domain, and therefore of hair cells, within the cochlea.

doi:10.1016/j.ydbio.2008.05.248

Program/Abstract # 233 Sox2 as a prosensory and proneural gene in the developing mouse cochlea Chandrakala Puligilla a, A. Dabdoub a, K.S. Cheah b, L.H. Pevny c, M.W. Kelley a a NIDCD/NIH, MD, USA b University of Hong Kong, Hong Kong c UNC, NC, USA

doi:10.1016/j.ydbio.2008.05.250

The mammalian cochlea is comprised of three main components; mechanosensory hair cells, non-sensory cells, and primary afferent neurons all of which are derived from cells within the otocyst. The Sox2 transcription factor is expressed in progenitor cells within the otocyst that become specified as prosensory or proneural. Here, we demonstrate that Sox2 expression becomes downregulated in hair cells as they differentiate due to a mutually antagonistic relationship between Sox2 and Atoh1, a bHLH transcription factor that is necessary for hair cell formation. Overexpression of Sox2 antagonizes hair cell formation, while overexpression of Atoh1 in cells that express Sox2 results in Sox2 downregulation and hair cell formation. In contrast, only 50% of cells co-transfected with Atoh1 and Sox2 develop as hair cells. These results were confirmed in vivo in hypomorphic Sox2EGFP/LP mice which express only 20% of the normal levels of Sox2. By comparison with WT cochleae, early differentiation and overproduction of hair cells are observed in Sox2 hypomorphs due to reduction in the antagonistic levels of Sox2 on Atoh1. In contrast with the biphasic role of Sox2 in sensory cell formation, its role in neuronal development is more direct. The cochlear spiral ganglion consists of bipolar neurons that connect hair cells to the cochlear nucleus. We show that Sox2 is expressed in these neurons and that the spiral ganglion neurons are absent in Sox2 mutants. Moreover, we demonstrate that non-sensory epithelial cells within the developing inner ear can be converted to a neuronal identity through overexpression of Sox2 indicating a role for Sox2 in neurogenesis in the inner ear.

microRNAs are required in the developing vertebrate lung, limb, and skin. We hypothesized that microRNAs are also required in the developing nervous system. Our analysis of microRNA levels during neural progenitor cell (NPC) differentiation in culture found rapidly rising levels of a brain-specific microRNA, miR-34a. Interestingly, this candidate has been shown by others to work downstream of p53 to promote cell cycle exit, particularly in dedifferentiating tumor cells. Based on these observations, we hypothesized that miR-34a modulates maintenance and/or differentiation of neural progenitor cells in mouse brain by controlling rate of cell cycle exit. In situ hybridization studies have shown that miR-34a is specific to neurons in the adult mouse brain. miR-34a overexpression decreased the fraction of NPCs in S-phase, and also repressed numblike, a key regulator of asymmetric divisions in these cells. These studies describe the role of a tumor suppressor miR in the developing nervous system.

doi:10.1016/j.ydbio.2008.05.249

doi:10.1016/j.ydbio.2008.05.251

Program/Abstract # 235 miR-34a modulates neural progenitor cell differentiation Sarah K. Fineberg a,b, Laboni L. Ghosh c, B.J. He a,b, Scott Q. Harper d, Beverly L. Davidson e a Molecular Physiology and Biophysics, Ohio State University, USA b Medical Scientist Training Program, Ohio State University, USA c Iowa Biosciences Advantage, Ohio State University, USA d Children's Hospital, Ohio State University, USA e Department of Internal Medicine, USA