The mechanisms by which proneural basic helix-loop-helix (bHLH) factors control neurogenesis have been characterized, but it is not known how they specify neuronal cell-type identity. Here, we provide evidence that two conserved serine residues on the bHLH factor neurogenin 2 (Ngn2), S231 and S234, are phosphorylated during motor neuron differentiation. In knockin mice in which S231 and S234 of Ngn2 were mutated to alanines, neurogenesis occurs normally, but motor neuron specification is impaired. The phosphorylation of Ngn2 at S231 and S234 facilitates the interaction of Ngn2 with LIM homeodomain transcription factors to specify motor neuron identity. The phosphorylation-dependent cooperativity between Ngn2 and homeodomain transcription factors may be a general mechanism by which the activities of bHLH and homeodomain proteins are temporally and spatially integrated to generate the wide diversity of cell types that are a hallmark of the nervous system.
Members of the T-box transcription factor family (Tbx) are associated with several human syndromes during embryogenesis. Nevertheless, their functions within the developing CNS remain poorly characterized. Tbx20 is expressed by migrating branchiomotor/visceromotor (BM/VM) neurons within the hindbrain during neuronal circuit formation. We examined Tbx20 function in BM/VM cells using conditional Tbx20-null mutant mice to delete the gene in neurons. Hindbrain rhombomere patterning and the initial generation of post-mitotic BM/VM neurons were normal in Tbx20 mutants. However, Tbx20 was required for the tangential (caudal) migration of facial neurons, the lateral migration of trigeminal cells and the trans-median movement of vestibuloacoustic neurons. Facial cell soma migration defects were associated with the coordinate downregulation of multiple components of the planar cell polarity pathway including Fzd7, Wnt11, Prickle1, Vang1 and Vang2. Our study suggests that Tbx20 programs a variety of hindbrain motor neurons for migration, independent of directionality, and in facial neurons is a positive regulator of the non-canonical Wnt signaling pathway.
Background: Neural stem cells (NSCs) are present in the adult mammalian brain and sustain lifelong adult neurogenesis in the dentate gyrus of the hippocampus. In culture, fibroblast growth factor-2 (FGF-2) is sufficient to maintain the self-renewal of adult NSCs derived from the adult rat hippocampus. The underlying signalling mechanism is not fully understood.
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