Sensory epithelia provide the link between the surrounding environment and its neuronal representation in the brain. The main olfactory epithelium (MOE) permits detection of volatile chemicals by selective activation of olfactory sensory neurons (OSNs), whose identity is defined by singular expression of an olfactory receptor gene (OR). Singular OR choice enables OSN maturation, defines the receptive field of the cell, and determines its axonal targeting to glomeruli in the olfactory bulb. Patterns of glomeruli activity are believed to represent the functional topographic map of odorant cues in the environment. Thus, expression of a singular OR is required for proper neuronal identity, axonal wiring, and odorant perception. Surprisingly, recent single cell RNA-Seq data suggest that individual immature neurons may express multiple OR mRNA transcripts, which is in direct conflict with the longstanding ?one-receptor one-neuron? hypothesis. Our work has identified the RNA binding protein Mex3a in immature OSNs as a post-transcriptional regulator that may repress OR transcripts from being translated before one OR is selected for singular expression. Genetic gain of function experiments assign Mex3a as a guardian of the immature neuron state, potentially by binding OR mRNAs directly to prevent their translation, or by targeting an entire class of transcripts such as cilia directed proteins. We propose to identify the direct RNA targets of Mex3a in the MOE, and determine how neuronal differentiation and OR choice are affected in genetic loss of function animals. These studies are poised to unveil a novel post-transcriptional mechanism for regulation of stochastic choice, and will also uncover gene regulatory networks responsible for maintaining progenitor states in sensory cells.
Neurons in the nose are specialized to detect a vast array of odors in the environment and relay that information to the brain. This project explores the post-transcriptional mechanisms that allow proper sensory cell maturation while assuring generation of neuronal diversity so that myriad odors can be detected. These studies will reveal generally applicable principals that control the development of the nervous and sensory systems and provide novel understanding of genetic perturbations linked to human neurodevelopmental and sensory disorders.
