The Roles of Sox2 in Stem and Progenitor Cells of the Mammalian Olfactory Epithelium
- Sanchez, Miguel Angel
- Advisor(s): Ngai, John
Abstract
Olfactory neurogenesis is essential in certain mammals, as they are dependent on the detection of odors to guide social behaviors, localize food, find mating partners, and avoid predators. The mammalian olfactory epithelium (OE) supports adult neurogenesis. Under homeostatic conditions, multipotent stem/progenitor cells, the globose basal cells (GBCs), contribute to neurogenesis to replace the constant turnover of sensory neurons in the neuroepithelium. The constant turnover of neurons at homeostasis means that a stem/progenitor cell population must be present to sustain neurogenesis throughout the life of the organism. Stem/progenitor cells must self-renew so that they are not exhausted during neurogenesis. Additionally, the adult OE has tremendous capacity for tissue regeneration following injury, making it an ideal model for the study of stem/progenitor cell regulation and neurogenesis. Following injury, the OE activates the quiescent, multipotent horizontal basal cells (HBCs), causing them to proliferate and differentiate into all of the cellular constituents of the OE. The Sox2 transcription factor is expressed in both HBCs and GBCs, and is a characteristic of stem cells in many tissues, including neurogenic niches of the of the central nervous system (CNS), namely the SVZ and SGZ. Sox2 has been identified as a key component in self-renewal and multipotency of NSCs (Ferri et al., 2004; Ellis et al., 2004; Pevny and Nicolis, 2010). Sox2 loss of function in NSCs of the CNS results in impairments in proliferation, loss of NSCs and neuronal progenitors, followed by a complete loss of neurogenesis, in both the embryonic and adult mouse brains (Ferri et al., 2004; Miyagi et al., 2008; Favaro et al., 2009). In the adult OE, Sox2 is expressed in HBCs, GBCs, and Sus cells. However, the functions of Sox2 in self-renewal and differentiation of HBCs and GBCs have remained largely unknown. To resolve the differences that underlie Sox2 function in HBC and GBC self-renewal, proliferation, and differentiation, targeted Sox2 ablation in transgenic mouse models were employed. Combined with lineage-tracing, fate mapping, pulse-labeling, and immunohistochemistry, the following was determined: (1) Sox2 is dispensable for HBC maintenance and their faithful self-renewal following injury. (2) HBCs require Sox2 to generate proliferative, self-renewing GBCs and neurons. (3) Sox2 is indispensable for steady-state maintenance of long-term, self renewing GBCs and neurogenesis. These findings not only underscore the necessity for Sox2 in maintaining an active progenitor pool that contributes to long-term neurogenesis, but highlight the functional differences Sox2 exerts on the HBCs and GBCs.