Grant: Project Grant

The extraordinary computing power that underlies the higher order cognitive functions of the human brain is largely centered in a region of the brain called the neocortex. The neurons that make up the neocortex are born in the embryonic period and must survive and function for an entire lifetime. Neural stem and progenitor cells are the building blocks of the neocortex, as they produce the neurons and glial cells that make up the brain during embryonic development. Our goal is to understand how neural stem and progenitor cells undergo dynamic changes in neurogenesis, which is the generation of new neurons, including alterations to mode, fate and pace of neurogenesis. To study the mode of neurogenesis, which can be direct or indirect, we use mouse models. To study the pace of neurogenesis, we use a human, 3D cell based system called a cortical organoid. We study human neurogenesis as it is protracted compared to rodent neurogenesis, occurring over a much longer time period. To understand how neural stem and progenitor cells differentiate into neurons, we focus on a group of genes called proneural genes. Proneural genes are evolutionarily conserved drivers of neurogenesis and are required for new neuron production in small invertebrate organisms such as the fruit fly and in mammals, such as mice and man. Proneural genes encode transcription factors, which are the proteins that turn genes 'on'. Here we examine how the ability of proneural transcription factors to turn on downstream genes is impacted by other interacting proteins in the neurogenic niche. We first examine how proneural transcription factor-partner protein complexes control the mode (aim 1) and fate (aim 2) of neurogenesis in the embryonic mouse brain. We then study how interactors control neuronal pace in human cortical organoids (aim 3). These studies will increase our foundational knowledge of brain development and aid the design of neuro-regenerative strategies.