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MicroRNA-mediated induction of neuronal cells [electronic resource]

Mammalian neurogenesis - an elagant process of producing extraodinarily diversified neuronal propulations - has been largely studied in the context of evoluationarily conserved signalling pathways and neurogenic transcription factors. Yet little is known about the roles of chromatin remodellers and regulatory RNAs, such as microRNAs, in the formation of neurons. We recently discovered that miR-9* and miR-124 instruct compositional changes of SWI/SNF-like BAF chromatin-remodelling complexes during murine nervous development, a process important for neuronal differentiation and function. Here I set out to directly test the neurogenic activity of these microRNAs in human non-neuronal cells. Together with Andrew Yoo, I showed that ectopic expression of miR-9/9* and miR-124 (miR-9/9*-124) in human dermal fibroblasts induces their conversion into neurons (chapter 2). Addition of neurogenic transcription factors such as NEUROD2, ASCL1 and MYT1L enhances the rate of conversion and the maturation of the converted neurons, whereas expression of these transcription factors alone without miR-9/9*-124 appeared ineffective. As a step closer to cell replacement therapy, I next showed that these microRNAs could directly convert human astrocytes into neurons, of which the subtype identity can be further biased by specfic neurogenic factors (chapeter 3). Collectively, these studies indicate that the genetic circuitry involving miR-9/9*-124 and BAF chromatin remodelling complex can have an instructive role in neuronal fate determination, and may form a neuronal ground state that can be further specified by different transciption factors and/or signalling pathways.