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. Similarly, mechanisms enabling tissue regeneration following injury in the adult nervous sysem
are incompletely understood.
In the vertebrate olfactory system, primary sensory neurons and other cell types 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 the properties of adult neural stem cells.
Following injury that results in destruction of all mature neurons and support cells in the olfactory epithelium,
adult stem cells are activated to reconstitute all cell types in this structure. Of particular interest are the
mechanisms that support regeneration of the olfactory epithelium following injury and whether and how they
differ from mechanisms subserving tissue homeostasis under normal conditions. Elucidation of these
regulatory networks is critical for understanding how mature neuronal and non-neuronal cell types are
generated from the adult tissue stem cell of the olfactory epithelium.
In this application we propose to investigate the cellular mechanisms and genetic pathways subserving the
reconstitution of the olfactory epithelium following injury. Specifically, we propose a unique suite of approaches
including single cell transcriptome profiling combined with rigorous statistical analysis, in vivo lineage tracing,
and genetic pertubations to (1) elucidate the mechanisms underlying injury-induced regeneration in the
olfactory epithelium stem cell niche and (2) establish the roles of canonical Wnt signaling and Sox2 in early
olfactory neurogenesis. Together these investigations will provide a model for understanding the mechanisms
regulating other neural stem cell types and lay the groundwork for the future development of treatments and
therapeutics to ameliorate neural tissue damage and degeneration.