The Notch signaling pathway is evolutionarily conserved. In the developing nervous system, Notch signaling is required at multiple stages to govern cell fate decisions, from the first segregation of neural precursors, to the terminal specification of cells including neurons and glia. Notch signaling strongly inhibits neurogenesis and triggers the differentiation of some types of glia including Schwann cells, M?ller cells, astrocytes, Bergmann glia, and radial glia. Furthermore, Notch signaling contributes to the maintenance of oligodendrocyte precursor cells as well as oligodendrocyte maturation and myelination. Radial glial cells are one of macroglial cell types and function as scaffolding cells for neuronal migration and neural progenitor cells. Importantly, previous study shows defective radial glia function in the developing brain is causative for cortical dysplasia, and the concomitant pathologies of epilepsy and mental retardation. Radial glial cells are also implicated as candidate stem cells of ependymoma, a brain tumor. Despite their functional importance, the molecular mechanism that underlies radial glial development has been poorly understood. In their studies examining the role of Notch signaling in radial glial formation in Xenopus laevis, the investigators have uncovered that Suppressor of Hairless [Su(H)], a transcription factor required for Notch signaling, is sufficient but not required for radial glial formation. Similar findings have been hinted at in mammalian studies, and this strongly suggests the existence of novel Su(H)-independent Notch pathway that is employed for radial glial development. To elucidate the molecular mechanism of Su(H)-independent pathway in radial glial formation, the investigators have identified B-cell leukemia/lymphoma 6 (BCL6) as a Notch-associated factor by coimmunoprecipitation with mass spectrometry analysis. BCL6 is a BTB/POZ-zinc-finger transcriptional factor and has been reported to be required for normal germinal center (GC) development. While BCL6 is expressed in the developing mammalian central nervous system, the role of BCL6 during embryogenesis still remains unclear. To test whether BCL6 is involved in Su(H)-independent Notch signaling pathway during radial glial development, the investigators propose to characterize the role of BCL6 in Su(H)-independent Notch signaling pathway during Xenopus radial glial formation in Specific Aim 1, and investigate the role of BCL6 in mammalian radial glial formation in Specific Aim 2.
| Sakano, Daisuke; Kato, Akiko; Parikh, Nisarg et al. (2010) BCL6 canalizes Notch-dependent transcription, excluding Mastermind-like1 from selected target genes during left-right patterning. Dev Cell 18:450-62 |
