Deciphering the role of C2H2 zinc finger transcription factors during primate neocortex development and evolution

The neocortex is a fascinating brain structure, as it is the seat of mammalian, and notably primate, higher cognitive abilities. In the primate lineage, different neocortex morphology, in form of size and folding differences, has evolved. The development of the neocortex, and particularly of the different neocortex morphology, depends primarily on the precise regulation of the activity and behavior of cortical neural stem and progenitor cells (cNPCs), a regulation that is primarily mediated by transcription factors. One of the largest transcription factor families is the C2H2 zinc finger transcription factors (C2H2-ZFTFs), which also significantly expanded during primate evolution. Previous studies suggest that these transcription factors could be important regulators of primate neocortex development and evolution. Here, I propose that differential expression of these C2H2-ZFTFs is one essential cause of the differences in neocortex morphology between different primate species. To address this hypothesis, I plan to first identify expression differences of C2H2-ZFTFs in cNPCs of different primate species by transcriptome analysis of fetal human, macaque, and marmoset neocortex. These differences will then be tested for a functional role in cNPCs using electroporation and stable genetic modification of brain organoids. Finally, for C2H2-ZFTFs with a functional role in cNPCs, the downstream gene regulatory network will be uncovered by identification of the indirect and direct targets using RNAseq and ChIP-exo of in vitro differentiated neural progenitor cells. This will lead to a better understanding of the role of C2H2-ZFTFs in the regulation of cNPCs, while also identifying their contribution to primate neocortex development and evolution that has led to different primate neocortex morphology. This is also likely to provide novel insights into the formation of cortical malformations (e.g., microcephaly or lissencephaly).