Regulation of Olfactory Stem Cells and Neurogenesis by Primary Cilia and the Hedgehog Pathway.

Stem Cells;Cilia;Neurogenesis;Olfaction;Regeneration;Pharmacy and Pharmacology;Health Sciences;Pharmacology

Joiner, AriellMartens, Jeffrey ;

University of Michigan

关键词: Stem Cells;    Cilia;    Neurogenesis;    Olfaction;    Regeneration;    Pharmacy and Pharmacology;    Health Sciences;    Pharmacology;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/120700/arieljoi_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

The olfactory epithelium (OE) is one of the few tissues to undergo constitutive neurogenesis throughout the mammalian lifespan. It contains multiple cell types including olfactory sensory neurons (OSNs) that are replaced by two populations of basal stem cells – frequently dividing globose basal cells (GBCs), and quiescent horizontal basal cells (HBCs). Strikingly, the mechanisms that control stem cell activation and proliferation, during normal OE homeostasis and in response to injury remain largely unexplored. My data indicate that HBCs possess primary cilia, cellular organelles that regulate the activity of multiple signaling pathways, including Hedgehog (HH) signaling. The HH pathway is required for the formation, survival, and activity of stem/progenitor cell populations in several adult tissues, making it an attractive candidate for HBC regulation. The goals of this dissertation are: 1) to investigate the role of primary cilia in HBC-driven olfactory neurogenesis and 2) to explore the contribution of HH signaling to HBC function.My data indicate that HBC-specific deletion of the ciliary gene Ift88 effectively abrogates primary cilia. Interestingly, the loss of HBC cilia did not affect HBC cell numbers or maintenance of the adult OE, but dramatically impaired the regeneration of OSNs following injury. Furthermore, the loss of cilia during development resulted in region-specific decreases in neurogenesis, implicating HBCs in in OE establishment. These results demonstrate a novel role for primary cilia in olfactory neurogenesis and suggest a role for primary cilia in HBC activation, proliferation, and differentiation. My data also demonstrate that HH pathway components are expressed in the adult OE. Specifically, the HH transcription factors, Gli2 and Gli3 are selectively expressed in HBCs, implicating HH signaling in the control of HBC function. Constitutive Gli2 activation in HBCs resulted in hyperproliferation and loss of neuronal cells, and also impaired OE regeneration following injury. Surprisingly, constitutive Gli2 repression in HBCs did not alter OE maintenance, but did impair injury-induced OE regeneration. These results suggest a novel role for HH signaling, and specifically Gli2, in HBC regulation during OE homeostasis and regeneration. Overall, this work defines novel roles for primary cilia and HH signaling in HBC-mediated regulation of the mammalian OE.