Role of Non-catalytic form of TrkC receptor in cell fate specification of neocortical progenitors

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Neocortical progenitors successively give rise to a heterogeneous population of neurons during development so that early progenitors generate deep layer neurons while late progenitors generate upper layer neurons. Understanding how this process is regulated is vital for understanding crucial aspects of neocortical evolution and ultimately development of the human neocortex. The program of corticogenesis has been shown to be intrinsically hard-wired within cortical progenitors, however molecular mechanisms that control the different potentials of early and late progenitors are not known. Recently, we discovered that the expression of TrkC T1, a splice variant of the neurotrophin receptor TrkC that lacks the intracellular kinase domain (non-catalytic TrkC), distinguishes early from late neocortical progenitors. In progenitor cells, TrkC T1 is expressed within a short temporal window that coincides with deeper layer neurogenesis and is down-regulated during upper layer neurogenesis. In vivo, down regulation of TrkC T1 expression in neocortical progenitors induces a reduction in the number of deep layer neurons while upregulation of TrkC T1 expression induces an increase in the number of deeper layer at the expense of upper layers neurons. In the current project proposal, we intend to identify the molecular mechanisms that act downstream of non-catalytic TrkC to control cell fate decisions in the developing neocortex.