Clonal architecture and genetic regulation of the developing mammalian cerebral cortex

Abstract

The mammalian brain is a remarkably intricate organ that starts out as a single layer of epithelial cells. Over the course of development, this single layer of cells grows into many layers of neurons and glia that differentiate into genetically-defined subtypes residing in different regions of the brain with different mature functions. While development is ongoing, it is challenging to study individual cells as they divide, differentiate, and migrate through the growing layers of tissue. However, it is possible to learn about this process indirectly through the use of multiple in vitro and in vivo models of mammalian brains. This thesis examines how brains develop at the single-cell level by first establishing a new technique to study the relationship between cell lineage and developmental gene expression in the mouse brain, as well as the gyrencephalic or folded ferret brain, which is more structurally similar to the human brain. In a subsequent chapter recently published in Developmental Cell, I show how we utilized specific patient mutations in the gene KIF26A to elucidate the developmental roles of this gene in cell migration, axon and dendrite growth, and apoptosis. For final chapter, published in 2021 in Neuron, I describe our work investigating changes in gene regulatory programs that are important for brain development over the course of mammalian and human-specific evolution.