| The complex neural circuitry of the mammalian nervous system arises from a small pool of neural precursors that, during development, sequentially gives rise to neurons, astrocytes and oligodendrocytes. Several molecular mechanisms and environmental stimuli regulate the expansion of the neural precursor pool and the subsequent generation of differentiated progeny. In this thesis, I sought to investigate whether post-transcriptional regulation plays a role in the development of mammalian neural precursors. In the first part of this thesis, I show that the double stranded RNA binding protein Staufen2 is part of a repressive complex, with Pumilio2 and DDX1, that prevents early differentiation of neural precursors into neurons by repressing the translation of neurogenic mRNAs such as prox1. In the second part of the thesis I show that Smaug2, a translational repressor, also prevents early generation of neurons by repressing nanos1 mRNA, which encodes another RNA-binding protein. I also show that nanos1 repression occurs by its inclusion in a P-body like granule with 4E-T, another known repressor of mRNA translation. In the last chapter I identify mRNAs associating with Smaug2 and I suggest that Smaug2 may have additional functions that are independent of nanos1 regulation and that unlike nanos1, which is regulated together by Smaug2 and 4E-T, the majority of Smaug2 mRNAs are regulated independently from 4E-T. Together, these studies suggest that several RNA-binding proteins are crucial regulators of cortical development and that they perform this role by forming several, largely independent, repressive RNA-protein complexes. I suggest that these repressive complexes prime neural precursors to generate progeny at the appropriate time by repressing proneurogenic mRNAs until the appropriate developmental cue. |
