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 the properties of neuronal stem cells. While distinct stages of the olfactory lineage have been identified with a limited set of molecular markers, much remains to be learned about the genetic programs that both define and regulate olfactory neurogenesis during development and regeneration. To date, nothing is known about the transcriptional networks regulating the multipotent olfactory progenitors, the earliest cells in the lineage. 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 role of the transcription factor p63 - a member of the p53 family of tumor suppressors - in olfactory stem cell regulation. Through whole genome transcriptome profiling and genetic loss-of-function analysis, we recently discovered that p63 is a key regulator of olfactory stem cell self-renewal and differentiation in vivo, similar to its established role in other epithelial stem cells. Here we propose to investigate the cellular and molecular actions of p63 in the olfactory stem cell. Specifically, we will (1) determine the role of p63 in the choice between self-renewal and differentiation;(2) determine whether p63 and its related family member p53 interact to regulate olfactory stem cell dynamics;and (3) characterize the p63-dependent transcriptional network regulating the olfactory stem cell by identifying the downstream targets of p63. Together these investigations will illuminate the cellular and molecular mechanisms regulating olfactory stem cell maintenance, proliferation and differentiation. Moreover, our studies 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.
The proposed research will define and characterize the genetic interactions regulating neurogenesis and tissue regeneration in the olfactory epithelium. This information is critical for an understanding of the causes of degenerative diseases and injuries resulting from the misregulation of these processes, and will lay the foundation for future strategies aimed at ameliorating neurodegenerative disorders and traumatic injuries by identifying new therapeutic targets and potential cell replacement therapies.
|Fletcher, Russell B; Das, Diya; Gadye, Levi et al. (2017) Deconstructing Olfactory Stem Cell Trajectories at Single-Cell Resolution. Cell Stem Cell 20:817-830.e8|
|Boesveldt, Sanne; Postma, Elbrich M; Boak, Duncan et al. (2017) Anosmia-A Clinical Review. Chem Senses 42:513-523|
|Gadye, Levi; Das, Diya; Sanchez, Michael A et al. (2017) Injury Activates Transient Olfactory Stem Cell States with Diverse Lineage Capacities. Cell Stem Cell 21:775-790.e9|
|Risso, Davide; Ngai, John; Speed, Terence P et al. (2014) Normalization of RNA-seq data using factor analysis of control genes or samples. Nat Biotechnol 32:896-902|
|Ferreira, Todd; Wilson, Sarah R; Choi, Yoon Gi et al. (2014) Silencing of odorant receptor genes by G protein ?? signaling ensures the expression of one odorant receptor per olfactory sensory neuron. Neuron 81:847-59|
|Ngai, John (2013) Intrinsic activity of odorant receptors guides sensory map formation. Cell 154:1186-7|
|Fletcher, Russell B; Prasol, Melanie S; Estrada, Jose et al. (2011) p63 regulates olfactory stem cell self-renewal and differentiation. Neuron 72:748-59|
|Campbell, Gordon R O; Baudhuin, Ariane; Vranizan, Karen et al. (2011) Transcription factors expressed in olfactory bulb local progenitor cells revealed by genome-wide transcriptome profiling. Mol Cell Neurosci 46:548-61|
|Scolnick, Jonathan A; Cui, Kai; Duggan, Cynthia D et al. (2008) Role of IGF signaling in olfactory sensory map formation and axon guidance. Neuron 57:847-57|
|Duggan, Cynthia D; DeMaria, Shannon; Baudhuin, Ariane et al. (2008) Foxg1 is required for development of the vertebrate olfactory system. J Neurosci 28:5229-39|
Showing the most recent 10 out of 11 publications