Figure 2.

A central unanswered question is how are the gradients of TFs in the VZ translated into positional information in the SVZ and CP, to generate cortical regions? We hypothesize that enhancers active in the VZ {E1, E2}, SVZ {E3, E4} and CP {E5, E6} are differentially bound by TFs that drive expression of region/layer-specific genes in post-mitotic cortical neurons. The enhancers serve as protein-binding modules that translate rostrocaudal gradients of TFs in cortical progenitors into region-specific expression in cortical neurons. In this simplified model, enhancers active in the SVZ (E3, E4) and CP (E5, E6) are primed in the VZ by TFs. A filled colored box symbolizes TF binding to the enhancer; an empty box symbolizes that the TF, which is no longer expressed, had previously bound that enhancer, and modified its epigenetic state. For instance, binding of a PAX6 in rostral VZ cells (where its concentration is highest) preferentially activates rostral VZ enhancers (E1) and not caudal VZ enhancers (E2) that are activated by EMX2 and COUPTF1. We postulate that PAX6, EMX2 and COUPTF1 will prime certain SVZ and CP enhancers, marking them epigenetically with modified histone marks of poised or active chromatin, thus passing on positional information to enhancers that are active in the SVZ and CP. Propagation of the VZ protomap into the SVZ and CP is carried out by TBR2, COUPTF1, TBR1 and BHLHB5.