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

新皮质祖细胞在发育过程中依次产生异质的神经元群体，早期祖细胞产生深层神经元，而晚期祖细胞产生上层神经元。了解这一过程是如何被调节的，对于理解新皮层进化的关键方面以及人类新皮层的最终发育至关重要。皮质发生程序已被证明是皮质祖细胞内在的硬连接，然而，控制早期和晚期祖细胞不同潜能的分子机制尚不清楚。最近，我们发现TrkC T1（一种神经营养因子受体TrkC的剪接变体，缺乏细胞内激酶结构域（非催化TrkC））的表达区分了早期和晚期的新皮质祖细胞。在祖细胞中，TrkC T1在较短的时间窗口内表达，与深层神经发生一致，在上层神经发生期间下调。在体内，新皮质祖细胞中TrkC T1表达下调导致深层神经元数量减少，而TrkC T1表达上调导致深层神经元数量增加，而上层神经元数量减少。在目前的项目提案中，我们打算确定非催化TrkC下游的分子机制，以控制发育中的新皮层中细胞命运的决定。

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.