Convergence of the notch, tgf-beta and sonic hedgehog pathways in neural progenitor cell specification and differentiation
Swetenburg, Raymond Lee
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One of the best studied fate switches in mammalian development is the specification and differentiation of cell types within the ventral neural tube, the precursor to the spinal cord. Unspecified cells experience a gradient of Sonic hedgehog (Shh) from the notochord and, later, the floor plate, which ultimately will become the complete motor control circuit responsible for all movement, both voluntary and involuntary. Initially, the transcription factor Olig2 is expressed under this Shh gradient in the ventral-most pool of cells. Within this group, more dorsal cells retain their Olig2 identity becoming the motor neuron progenitor domain (pMN), while more ventral cells, under the influence of increased Shh signaling, will express the Olig2-repressive transcription factor Nkx2.2 and become the p3 domain. Both progenitor pools initially generate neurons by self-preserving asymmetric divisions: motor neurons from the pMN and V3 interneurons from the p3. Later in development, these cells undergo a fate switch, where the sharp division between the domains becomes blurred and Olig2 and Nkx2.2 eventually become co-expressed as oligodendrocyte progenitor cells (OPC). The juxtacrine Notch-Delta pathway is critical throughout neural development, though the results of gain- and loss-of-function experiments have shown it to be extremely context-dependent. For instance, Notch inhibition has been demonstrated to increase pMN at the expense of p3, increase MN at the expense of pMN or increase OPC at the expense of pMN, depending on the specific timing and method of inhibition. We therefore asked how Notch inhibition might regulate the Olig2 protein within the context of pluripotent stem cell towards these cell types. In this work, we show that Notch inhibition destabilizes Olig2 during neurogenesis by a post-transcriptional mechanism which can be rescued by Tgf-β signaling. Further, we explore the intricate push and pull of Shh, Notch-Delta and Tgf-β in the derivation and specification of pMN, p3, MN and OPC in which these signals can have multiple targets and modulate cell differentiation in complex, and sometimes opposing, manners. We have identified novel and diverse paradigms for Olig2 regulation throughout the course of differentiation with implications for stem cell biology and future models of disease and development.