Wednesday, January 15, 2025
1/15/2025
PROJECT SUMMARY/ABSTRACT The incredible specificity with which we can discern a vast diversity of smells emerges from how olfactory sensory neurons (OSN) express olfactory receptor (OR) genes. These OR genes encode the proteins that bind chemical odorants. Each OSN stochastically transcribes only one allele of an OR gene. An OSN can choose to express any one of the approximately 1400 OR genes or 2800 alleles. There is no one to one relationship between an odorant and an OR as a combination of ORs are involved in the detection of one odorant. Thus, the diversity of ORs expressed is important to the main olfactory epithelium’s (MOE) ability to detect a vast range of smells. The choice of an OR gene occurs as OSN progenitors mature into an OSN. Recent work has revealed remarkable remodeling of the local chromatin and co-expression of multiple OR genes during this period, but the molecular mechanisms governing these processes and their connection to a singular OR allele expression in a mature OSN remain unknown. We show that testis expressed 15 (Tex15), a protein that has only been studied in the testes where it regulates methylation and silencing of transposons, is crucial for stochastic OR gene choice. We find that when Tex15 is knocked out there is a dramatic reduction in the diversity of expressed OR genes with a few OR genes dominating stochastic choice. Strikingly, Tex15 is only transiently expressed in OSN progenitors during a period of OR co-expression. Our central hypothesis is that Tex15 is epigenetically controlling stochastic OR gene choice, either by regulating DNA methylation or other aspects of OR gene chromatin structure. Aim 1 will determine whether Tex15 is required for transient co-expression of multiple OR genes in OSN progenitors. In aim 2, we will determine whether Tex15 protein binds to OR genes. Finally in aim 3, our experiments on primary OSNs from Tex15 null mice will determine how gene repression is mediated in OSN progenitors – through methylation or deposition of repressive heterochromatin. Together, these experiments will elucidate a novel aspect of how OSNs come to stochastically choose a single OR and how Tex15 gene and protein guides this specific yet diverse choice. We anticipate this project will uncover new and/or unexpected role for Tex15 in the MOE. This will also reveal the key molecular underpinnings for how our sense of smell develops and may provide important insight to further understand the mechanisms of smell disorder. The proposed fellowship will train this applicant in several innovative techniques in biochemical, cellular, molecular, and computational neuroscience. The established faculty-student mentorships will ensure proper scientific and professional training necessary to become a successful, independent sensory and computational neurobiologist.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).