Molecular mechanisms of neural tube closure and neuron-radial glial signaling during neuronal migration

To identify neuronal signals regulating radial glial cell development and function, I analyzed the expression and transcriptional control of Brain Lipid Binding Protein (BLBP), a gene previously shown to be induced in radial glia and astrocytes by migrating neurons. Mapping of the BLBP promoter in transgenic mice established that activation of the Notch pathway is the critical signal required for induction of BLBP in radial glia and Bergmann glia supporting neuronal migration, and that Notch signaling works in conjunction with additional factors to regulate the complex temporal and spatial pattern of BLBP expression. Together with previous work showing that activated Notch induces BLBP in vivo, these results establish that BLBP is a direct target of Notch signaling in the developing CNS, making it the first nervous system-specific Notch target yet identified. Furthermore, the requirement of Notch signaling (which is known to control cell fate decisions) in the dynamic regulation of BLBP during cortical neurogenesis and cerebellar granule cell migration suggests that this pathway plays a dual role as both regulator of cell fate and mediator of neuronal migration. I also examined the expression and function of 10-formyltetrahydrofolate dehydrogenase (FDH), a gene whose expression in the postnatal cerebellum was known to match that of BLBP. Unlike BLBP, FDH is not induced in radial glia until they become gliogenic, suggesting it does not play a role in supporting neuronal migration. However, I found that in addition to widespread glial expression during the postnatal period, FDH is also specifically expressed in radial glia flanking the ventral and dorsal midlines immediately following neural tube closure. Consistent with its known role as a suppressor of proliferation, regions expressing FDH are largely devoid of proliferating cells. Although FDH deficient mice do not develop neural tube defects (NTDs), these results provide the first evidence for restricted expression of a folate metabolic enzyme in the developing neural tube, and suggest that regulation of cell division during neurulation may be mediated in part through localized control of folate-dependent reactions. In addition, these findings suggest that exogenous folate might rescue human NTDs by modulating the activity of these localized pathways.