The generation of neuronal diversity in the nervous system requires the specification and differentiation of a multitude of cellular lineages. Successive developmental programs control the generation of individual neuronal types, cell migration, axon extension, and ultimately the formation of functional synaptic connections. The specific genetic programs underlying the differentiation of mature neurons from their progenitors remain incompletely characterized, in part because of the difficulty in studying neuronal progenitor cells in their native environments.

In the vertebrate olfactory system, primary sensory neurons are continuously regenerated throughout adult life via the proliferation and differentiation of multipotent neural progenitor cells. This feature makes the olfactory system particularly amenable for studies on adult neurogenesis and the properties of neuronal stem cells. Olfactory receptor neurons normally turn over every 30-60 days and are replaced through the proliferation and differentiation of multipotent progenitor cells: normally quiescent stem cells known as horizontal basal cells (HBCs) and proliferative progenitors known as globose basal cells (GBCs). Following injury that results in the destruction of mature cells in the olfactory epithelium, the HBCs proliferate and differentiate – using GBCs as intermediates – to reconstitute all cellular constituents of this sensory epithelium, including the olfactory receptor neurons (ORNs), sustentacular cells (Sus) and cells of the Bowman's Gland (BG). The regenerative capacity of the olfactory epithelium represents a powerful and experimentally accessible paradigm for understanding the regulation of neural stem cell function under normal conditions and during injury-induced regeneration. While distinct stages of the olfactory lineage have been identified, however, much remains to be learned about the genetic programs that both define and regulate olfactory neurogenesis during development and regeneration. Moreover, virtually nothing is known about the transcriptional networks regulating the HBCs and GBCs, the adult tissue stem cells of the postnatal olfactory epithelium.

Current projects are using a variety of approaches to elucidate the molecular and cellular mechanisms regulating olfactory stem cells and olfactory neurogenesis in the mouse. In one area of inquiry, using conditional genetic knockouts we are investigating the roles of certain transcription factors – e.g., p63 – and intracellular signaling pathways in promoting stem cell self-renewal, proliferation and differentiation. Other studies are using clonal analysis in vivo to determine how patterns of symmetric and asymmetric cell division support stem cell renewal and tissue maintenance. Finally, we are developing and applying single cell RNA-Seq and other genomics technologies to elucidate the developmental trajectories of cells as they transition from early stem cell states, through intermediate progenitors and then through terminal differentiation.

Together our studies provide a model for understanding the mechanisms regulating neural stem cells and lay the groundwork for the future development of treatments and therapeutics to ameliorate tissue damage and degeneration in the nervous system.