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.

Public Health Relevance

The proposed research will define and characterize the genetic interactions regulating neurogenesis during injury-induced 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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC007235-12
Application #
9593504
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Sullivan, Susan L
Project Start
2004-12-15
Project End
2022-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
12
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California Berkeley
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704
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Fletcher, Russell B; Das, Diya; Ngai, John (2018) Creating Lineage Trajectory Maps Via Integration of Single-Cell RNA-Sequencing and Lineage Tracing: Integrating transgenic lineage tracing and single-cell RNA-sequencing is a robust approach for mapping developmental lineage trajectories and cell fate cha Bioessays 40:e1800056
Boesveldt, Sanne; Postma, Elbrich M; Boak, Duncan et al. (2017) Anosmia-A Clinical Review. Chem Senses 42:513-523
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
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

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