UCSF

Development of the human cortex is a complex process that requires tightly controlled spatiotemporal regulation of gene expression. Genetic variation or altered regulatory dynamics can impact downstream protein function, which often leads to neurodevelopmental disorders (NDDs). These NDDs are widespread in genetic etiology and trait presentation, and often are sex biased in diagnosis. While the last few decades have identified hundreds of high confidence risk genes implicated in these NDDs, the convergent protein biological functions impacted by mutations in these genes, as well as the sex bias in risk, is still unclear. Here, I present two main chapters aimed at understanding the complex genetic mechanisms that give rise to NDDs. First, I show that genetic variation across risk genes gives rise to convergent rewiring of protein-protein interactions, using the FOXP1-FOXP4 interaction as an example. I highlight a novel, necessary role for FOXP4 in driving the developmental phenotypes associated with FOXP1 mutations. Then, I highlight sex differences in the midgestation cortex, identifying critical sex-biased gene expression and regulatory programs that underlie sex-specific mutational burden identified in NDD cohorts. This work is preceded by a literature review of the critical and novel roles of the morphogen retinoic acid during cortex development and its relation to NDD biology. Together, this work takes important steps forward in understanding how genetic variation leads to altered neurodevelopment, and therefore NDD vulnerability, at the molecular, cellular, and developmental scale.