Molecular Mechanisms Controlling Differentiation and Circuit Formation of Vomeronasal Sensory Neurons

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SUMMARY The nervous system is composed of thousands of different neuronal cell types. Neuronal identity and connectivity is defined by the expression of specific gene batteries. How neuronal identity is initiated and maintained is central to understand the molecular causes underlying neurodegenerative diseases. Olfactory dysfunctions often occur in aging, metabolic disorders, and numerous neurological disorders, including depression, Parkinson’s disease, multiple sclerosis, schizophrenia and dementia. Understanding what signals control terminal differentiation, expression patterns, plasticity, and homeostasis of olfactory neurons will fill a critical gap in knowledge. Our proposed studies will identify key mechanisms that underlie neuronal identity, axonal targeting and homeostasis of a specialized chemosensory epithelium. Our overall objective will delineate the molecular connections between olfactory deficits and neurological dysfunctions. The vomeronasal organ (VNO) is a specialized olfactory subsystem responsible to detect pheromones. While humans do not have a functional VNO, the human olfactory epithelium shares some characteristics with the VNO. As a model system, the VNO has a simple cellular structure with a small number of stem/progenitor cells that generate new sensory neurons throughout life. We chose to use this simplified model system to study mechanisms that control neurogenesis, neuron differentiation, cellular plasticity and homeostasis across postnatal life. The neuro-epithelium of the VNO is composed of two main classes of neurons that selectively express receptors encoded by two vomeronasal receptor (VR) gene families: V1R and V2R. While both neuronal types originate from a common pool of progenitor cells, V1R and V2R expressing neurons localize to different areas within the VNO and project to different areas of the accessory olfactory bulb. Our central hypothesis states that the transcription factor tfap2e (AP2e) controls basal VSN’s identity, cell composition of the VNO and its connectivity to the brain. We propose that the vomeronasal sensory neurons retain a high level of cellular plasticity that allows them to be reprogrammed even after terminal differentiation. Moreover, we propose that bone morphogenic protein BMP signaling gradients established by BMP affinity to collagen IV (5, 6), in the basement membrane, initiate the basal differentiation program, AP2e expression and maintenance of the basal VSNs genetic identity throughout life. Our innovative approach will exploit state of the art mouse genetics, 2D and 3D imaging, next generation sequencing, chromatin immunoprecipitation (Chip)-seq, bioinformatics and behavioral testing to uncover the mechanisms that define and maintain the identity of chemosensory neurons in postnatal animals. The proposed research is significant as to understand critical gene regulatory networks in a specialized chemo-sensory epithelium and how changes in morphogenic signaling in postnatal animals affect its cellular composition, tissue homeostasis and neuronal connectivity and to identify mechanisms underlying chemosensory decline and neurodegeneration in humans. The findings from our proposed studies may produce therapeutic strategies to improve the human condition. !