Cell Type-Specific Contributions of FOXP1 to Human Cortical Development

The human neocortex consists of diverse cell types that are genetically pre-programmed to organize themselves in a human-specific manner throughout development. Some of the human specific features are reflected in the composition and behavioral patterns of cell types under strict spatiotemporal guidance by gene regulators such as transcription factors, which are acquired through evolution. Any defects in early cortical development can be detrimental and often result in irreversible neurodevelopmental disorders (NDDs). In our study, we wanted to understand human cortical development through a transcription factor, FOXP1, whose mutant forms are implicated in autism spectrum disorder (ASD) and intellectual disability (ID). FOXP1 is enriched in the human basal radial glial cells (bRGCs) and intermediate progenitor cells (IPCs) in the developing neocortex. These cell types are uniquely capable of sustained self-renewal and neurogenesis during early corticogenesis and rapidly decrease in number in later neurogenesis. I hypothesize that FOXP1 regulates gene expression programs in these specific cell types for the proper development of the neocortex. Progress in learning about the role of FOXP1 in different cell types in early corticogenesis has been limited due to technical challenges. However, with the advent of human brain developmental model systems and single-cell technologies, we can successfully interrogate cellular and molecular mechanisms in the rapidly developing human neocortex at single cell resolution. In this thesis, I present work I have done to understand human cortical development in the context of evolution and developmental disorders through the molecular window of FOXP1. In chapter 1, I summarize our current understandings on human neocortical development. This is a modified version of a review article I wrote summarizing scientific findings from many primary publications and several in-depth review articles on important topics, such as cellular and molecular mechanisms governing cortical progenitor proliferation, cell lineage progression, neuronal specification, and arealization, across multiple gyrencephalic and lissencephalic species. Chapter 2 is a literature review on the role of FOXP1 in corticogenesis and FOXP1-relevant NDDs. The contents in chapter 1 and 2 are designed to provide sufficient background information for my experimental hypothesis, design, results and discussion that are presented in chapter 3. Lastly, chapter 4 contains additional results, discussion and future directions, which includes my opinions and criticisms on my own work as well as recommendations for future experiments.