The long-range objective of this research proposal is to understand the molecular mechanisms that regulate the sequential onset of neurogenesis and gliogenesis during development of the mammalian central nervous system (CNS). We and others have recently found that CNS progenitor cells during the neurogenic period fail to differentiate into glia even when treated with potent glial-inducing factors. This observation led us to hypothesize that cellular properties intrinsic to CNS progenitors during the neurogenic phase negatively modulate glial differentiation factors in order to prevent precocious gliogenesis, thereby maintaining the sequential onset of neuronal and glial differentiation. To test this hypothesis we focused our studies on the regulation of one of the major astrogliogenic pathways, the LIF-induced JAK-STAT pathway. The crucial role of this pathway in CNS astrocyte differentiation is manifested by impaired astrogliogenesis in mice with single gene knockouts of various components of the pathway. Our preliminary studies suggest that activation and function of JAK-STAT signaling is inhibited in cultured cortical progenitors during the neurogenic period. In this study, we will further examine whether the lack of astrogliogenesis during the neurogenic period results from inhibition of the JAK-STAT pathway during cortical neurogenesis in vivo, and whether altered activation of STAT signaling leads to delayed or precocious onset of astrogliogenesis. Our studies will attempt to address how the various components of or related to the JAK-STAT pathway are involved in the downregulation of astrogliogenic signaling during the neurogenic period. We also hope to outline a more detailed time course and sequence of events for the developmental regulation of the various components of the pathway. In sum, this study will help to establish evidence that the astrogliogenic JAK-STAT pathway is indeed suppressed during cortical neurogenesis, which will be important for future mechanistic studies determining how gliogenic pathways are suppressed during neurogenesis and how this suppression is overcome when cells become gliogenic. A complete understanding of these mechanisms will eventually allow us to more fully understand how cell fate determination and the sequential onset of neurogenesis and gliogenesis is achieved in the developing CNS.
| Zhao, Jing; Lin, Quan; Kim, Kevin J et al. (2015) Ngn1 inhibits astrogliogenesis through induction of miR-9 during neuronal fate specification. Elife 4:e06885 |
| Wu, Hao; Xu, Jun; Pang, Zhiping P et al. (2007) Integrative genomic and functional analyses reveal neuronal subtype differentiation bias in human embryonic stem cell lines. Proc Natl Acad Sci U S A 104:13821-6 |
| He, Fei; Sun, Yi E (2007) Glial cells more than support cells? Int J Biochem Cell Biol 39:661-5 |
| He, Fei; Ge, Weihong; Martinowich, Keri et al. (2005) A positive autoregulatory loop of Jak-STAT signaling controls the onset of astrogliogenesis. Nat Neurosci 8:616-25 |
| Fan, Guoping; Martinowich, Keri; Chin, Mark H et al. (2005) DNA methylation controls the timing of astrogliogenesis through regulation of JAK-STAT signaling. Development 132:3345-56 |
