The overall goal of this proposal is to elucidate the molecular mechanisms that control the production of neurons in the vertebrate central nervous system (CNS). The CNS of adult vertebrates is composed of a vast number of functionally distinct neuronal types that occupy specific and reproducible positions within the brain and spinal cord. Throughout the developing CNS, individual neurons are generated from proliferative precursors in a precise spatial and temporal order. The correct implementation of this order involves tight control over the transition from dividing multipotent precursors to newborn neurons with distinct phenotypic characteristics. Despite the central importance of this transition in neurogenesis, it is currently unclear how many steps are involved and whether or how they are linked. The spinal cord represents an ideal model system in which to examine the molecular mechanisms controlling the differentiation and diversification of neuronal types in the CNS. During neurogenesis in the spinal cord, studies show that Prox1 expression is restricted exclusively to post-mitotic, pre-migratory interneuron precursors located within a sub-ventricular zone (SVZ), but is specifically excluded from the motoneuron-generating domain. Later, at mid-gestation, Prox 1 is expressed in diverse neuronal and glial lineages. The expression of a number of other factors, including those that function as post-mitotic neural determinants, overlap with Prox1 in SVZ cells. These findings suggest that Prox1 is part of a genetic program that is important for normal neurogenesis, and that it functions to determine the unique characteristics of distinct neuronal populations in the spinal cord. To test this, both in-vitro and in-vitro approaches will be used to define the contribution of Prox1 and related factors to neurogenesis. These studies will provide important insights into the molecular mechanisms that control the genesis and differentiation of neurons in the vertebrate spinal cord, a subject with direct relevance to the development of therapeutic approaches for treating human patients with CNS injuries and degenerative disorders.
| Misra, Kamana; Mishra, Kamana; Gui, Hongxing et al. (2008) Prox1 regulates a transitory state for interneuron neurogenesis in the spinal cord. Dev Dyn 237:393-402 |
| Gui, Hongxing; Li, Shike; Matise, Michael P (2007) A cell-autonomous requirement for Cip/Kip cyclin-kinase inhibitors in regulating neuronal cell cycle exit but not differentiation in the developing spinal cord. Dev Biol 301:14-26 |
| Lei, Qiubo; Jeong, Yongsu; Misra, Kamana et al. (2006) Wnt signaling inhibitors regulate the transcriptional response to morphogenetic Shh-Gli signaling in the neural tube. Dev Cell 11:325-37 |
