UCLA

One of the key challenges of neural development is achieving the precise balance between progenitor self-renewal and differentiation. The production of early born neurons must be controlled such that the necessary numbers are generated without depleting the pool of progenitors for subsequent glial differentiation. This work reports the identification of two transcription factors, PLZF and RP58, as pivotal factors in the preservation of neural progenitor cells in the developing spinal cord through the period of neurogenesis. PLZF has been previously shown to promote the maintenance of both hematopoietic and male germline stem cells. This work will demonstrate that PLZF is expressed within a central domain of the developing spinal cord of chick and mouse embryos, that it is sufficient to oppose neuronal differentiation, and that its loss results in compromised progenitor maintenance and excessive neuron formation. Furthermore, it will be shown that PLZF functions in part by promoting the expression of FGF receptor 3 and thereby enhancing neural progenitor receptivity for the pro-progenitor FGF signaling pathway. Unlike PLZF, previous research has indicated that RP58 acts to promote cellular differentiation in the context of neocortical, hippocampal, and cerebellar development. However, in the context of the developing spinal cord, RP58 acts as a potent anti-differentiation factor. RP58 misexpression results in a greatly expanded neural progenitor pool whereas its reduction through RNAi knockdown results in rapid neuronal differentiation. This work will propose that this divergent activity of RP58 in the two fundamental regions of the CNS can be explained as different manifestations of the same gene regulatory module achieving different effects depending on the relative order in which its component parts are activated. Both PLZF and RP58 are members of the BTB-ZnF family of transcription factors, a family previously with only a limited known role in the development of the CNS. This work will close with a consideration of the prospects of PLZF and RP58 not only being important factors in maintaining neural progenitor cells, but as potential forerunners of a previously unappreciated family of spinal developmental regulators.