Mammalian nervous systems are made up of many specialized types of neuronal and non-neuronal cells. How are these diverse cell types generated over development and, once generated, how do they maintain their specialized identities? To address these questions, my lab studies the gene regulatory mechanisms that control cellular identity in the mouse olfactory system.
In mammals, most smells are detected by olfactory sensory neurons expressing olfactory receptors (ORs). Mammals have evolved a large repertoire of ORs to enable the detection of many diverse environmental odorants. The mouse genome encodes over 1,200 OR genes, and the expression of these genes is under the control of a specialized gene choice mechanism. This mechanism ensures that each olfactory sensory neuron expresses only one allele of one OR gene. This singular choice organizes the olfactory system; the OR expressed by each neuron determines the set of odorants it recognizes and the downstream synaptic targets that it innervates. The OR gene chosen by each olfactory neuron appears to be random, which is consistent with behavioral responses to most odorants being plastic and learned through experience. Yet, some odorants elicit innately aversive or attractive behavior, implying a mechanistic connection between the expression of specific ORs and functionally distinct cell fates.
My lab combines genomic and molecular genetic approaches to investigate the gene regulatory mechanisms that control olfactory receptor gene choice and connect this gene choice to olfactory neuron identity. In particular, we aim to synthesize information across multiple scales, from transcription factor binding to chromatin state to nuclear architecture, to better understand how stochastic and epigenetic mechanisms help the developing olfactory system to reliably generate diverse cell-types. We are currently investigating the developmentally regulated establishment of exquisitely specific, long-range and interchromosomal interactions between OR gene enhancers, as well as the mechanisms that lead to the transcriptional activation of specific OR genes. We hope that this work will reveal how specific odorants are genetically programmed to trigger innate behaviors, and provide insights into how mechanisms that generate cellular diversity are able to coordinate cell identity and cell function.