Molecular mechanisms regulating mitral cell development

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DESCRIPTION (provided by applicant): The olfactory bulb (OB) is the first relay station of olfactory information in the central nervous system (CNS). The general laminar organization and elaborate morphologies of OB projection neurons, mitral/tufted cells, have been well known for several decades, but we continue to lack insight into their developmental mechanisms. Previous studies revealed the timeline of anatomical changes of developing mitral cells. The next step is to understand the molecular determinants and pathways regulating the specific anatomical changes occurring during mitral/tufted cell development, which is the long-term goal of this project. To accomplish this goal, I have established a novel method to manipulate molecular expression in subsets of developing mitral cells. Using this method, this proposal seeks to investigate the roles of several candidate molecules in mitral cell development. The candidate molecules are three transcription factors (Tbr1, Tbr2, Tbx21), an extracellular matrix molecule (Reelin), a transmembrane protein (Protocadherin21), and a synaptic vesicle protein (vGluT1). All of these candidate molecules have been selected because they are specifically expressed by mitral/tufted cells in developing OB. In Aim 1, the temporal expression pattern of candidate molecules in developing mitral cells will be established. In Aim 2, the fate of mitral cell precursors in the absence of Tbr1 or Tbr2 will be determined. In Aim 3, I will test hypotheses regarding the roles of Tbx21, Reelin, Protocadherin21, and vGluT1 in morphological development and/or synapse formation of mitral cells. These studies will provide us with new significant insights into molecular determinants and pathways working in developing mitral cells, which can then serve as a stepping stone to further research. I believe that this will become one of the leading works for neuronal circuitry formation during development of both the OB and elsewhere in the CNS where these molecules are expressed. PUBLIC HEALTH RELEVANCE: Olfactory information is transmitted to diverse brain regions through mitral/tufted cells in the olfactory bulb. Several developmental disorders also have olfactory dysfunctions: for example, many Asperger's syndrome children have hyperosima (increased ability to smell) or hyposmia (reduced ability to smell); and Kallmann syndrome patients have anosmia (inability to smell). The general goal of this project is to understand the developmental mechanisms of mitral/tufted cells which could help in finding a cure of these olfactory dysfunctions.