Coordination of projection neuron fate and position by let-7

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Project Summary: The central nervous system contains a myriad of different cell types that receive and integrate information from the environment to generate the appropriate biological responses. Failure to produce the right composition of neuronal subtypes or defects in their localization can result in several mental and physical conditions that range from cognitive disorders to severe brain malformations. In the neocortex, a specialized pool of multipotent cells -called radial glial cells- gives rise to all the different populations of projection neurons in a conserved sequence. Importantly, early born projections neurons localize at the apical side of the cortical plate whereas later born neurons localize atop of their predecessors. Despite the strong correlation between projection neuron fate identity and position, the molecular mechanisms involved in such correlation remain elusive. MicroRNAs (miRNAs) have recently been uncovered as strong cell fate determinants and we and others have shown that let-7 expression in radial glia cells promotes the neurogenesis of late born cortical projection neurons. Importantly, we further demonstrate that let-7 expression positive correlates with projection neuron location in upper cortical layers (i.e., closer to the pial surface). Our preliminary data show that let-7 regulates neuron migration by opposing the expression of Rbx2, a core member of the E3 ubiquitin ligase CRL5, previously identified as a key factor to end projection neuron migration. Thus, we hypothesize that elevated expression of let-7 in late-born projection neurons reduces the activity of CRL5, promoting neuron migration. The proposed research will identify let-7 as the first coordinator of neural progenitor competence and projection neuron migration/localization, and unveil its molecular mechanism of action.