Role of post-transcriptional regulation on cortical cell fate specification

Project Summary: The central nervous system contains a myriad of different cell types that, in the right numbers and at the right positions, receive and integrate information from the environment to generate the appropriate biological responses. Failure to produce the right composition of cells can result in several mental and physical diseases that range from cognitive disorders to severe brain malformations. In the neocortex, a specialized pool of neural progenitors -called radial glial cells- gives rise to all types of projection neurons in a conserved temporal sequence. The textbook’s view has been that the ability of the neural progenitors to produce different subtypes of neurons is controlled by an intrinsic cascade of transcription factors that restrict progenitor competence over time. However, there are reasons to question this model and in fact, the molecules responsible for the synchronization of fate acquisition with developmental time remain elusive. Importantly, published and preliminary data indicate that microRNA (miRNA) levels also affect neuron fate determination in a cell- autonomous manner, highlighting the previously overlooked importance of posttranscriptional mechanisms in cortical development. Here, we propose to unbiasedly uncover the dynamics of miRNA expression and the mRNAs targeted by miRNAs pairs in neural progenitors over time using miR-eCLIP. We will further unveil relevant molecular mechanisms regulated by miRNA-targeted mRNAs, and, in particular, their effects on RNA methylation and how such RNA modification affects PN fate specification. Overall, the proposed research will define the miRNAs and their target mRNAs involved in cortical cell fate acquisition and shed light on the molecular mechanisms regulated by this important post-transcriptional mechanism.