Temporal Patterning and Generation of Neural Diversity in Drosophila Type II Neuroblast Lineages

Abstract

The central nervous system (CNS) has an astonishing diversity of neurons and glia. The diversity of cell types in the CNS has greatly increased throughout evolution and underlies our unique cognitive abilities. The diverse neurons and glia in the CNS are made from a relatively small pool of neural stem cells and progenitors. Understanding the developmental mechanisms that generate diverse cell types from neural progenitors will provide insight into the complexity of the mammalian CNS and guide stem cell based therapies for brain repair. Temporal patterning, during which individual neural progenitors change over time to make different neurons and a glia, is essential for the generation of neural diversity. However, the regulation of temporal patterning is poorly understood.

Human outer subventricular zone (OSVZ) neural stem cells and Drosophila type II neural stem cells (called neuroblasts) both generate transit-amplifying intermediate neural progenitors (INPs). INPs undergo additional rounds of cell division to increase the number of neurons and glia generated in neural stem cell lineages. However, it is unknown whether INPs simply expand the numbers of a particular cell type or make diverse neural progeny. In this dissertation, I show that type II neuroblast lineages give rise to extraordinary neural diversity in the Drosophila adult brain and contribute diverse neurons to a major brain structure, the central complex. I find that INPs undergo temporal patterning to expand neural diversity in type II lineages. I show that INPs sequentially generate distinct neural subtypes; that INPs sequentially express Dichaete, Grainyhead, and Eyeless transcription factors; and that these transcription factors are required for the production of distinct neural subtypes. Moreover, I find that parental type II neuroblasts also sequentially express transcription factors and generate different neuronal/glial progeny over time, providing a second temporal identity axis. I conclude that neuroblast and INP temporal patterning axes act combinatorially to specify diverse neural cell types within adult central complex; OSVZ neural stem cells may use similar mechanisms to increase neural diversity in the human brain.

This dissertation includes previously published co-authored material.