A key question in neurobiology is how individual neurons precisely connect with each other to form functional circuits during development. Understanding the mechanisms of neural circuit assembly in the mammalian brain may provide insights into the etiology of human brain disorders. In the mammalian brain, each neuron on average forms connection with thousands of other neurons. The assembly of these complex circuits depends on cell-cell communication during many steps of neural development. In the previous two cycles of this grant, we have focused on developing MADM (Mosaic Analysis with Double Markers) in mice. MADM labels with two distinct colors isolated individual neurons or groups of neurons that share a common lineage. At the same time, MADM can render neurons labeled with one of the colors homozygous mutant for a gene of interest and neurons labeled with the second color wild type as internal controls. MADM has allowed researchers to examine gene function in mammalian neural development (as well as other processes) with single-cell resolution, and enabled many new discoveries. In this renewal, we will utilize MADM and other tools we have developed in the previous grant cycles to study cell-cell communications in neural circuit assembly in the mouse brain. Specifically, we focus on two classes of proteins: neurotrophin receptors and teneurins. Using MADM analysis of the neurotrophin receptor TrkC, we have previously shown that sparse but not global knockout of TrkC in Purkinje cells reduces dendritic growth and branching, suggesting a competitive mechanism for dendrite morphogenesis. We will investigate the cellular mechanisms by which TrkC-mediated competitive dendrite morphogenesis using in vivo imaging, test whether postsynaptic activity required for Purkinje cell dendrite development, and the relationship between activity and TrkC signaling. We will also explore the function of neurotrophin receptor TrkB in neuronal morphogenesis. From our studies in Drosophila olfactory circuit assembly, we identified two teneurins, which are evolutionally conserved type II transmembrane proteins, that instruct synaptic partner matching via homophilic attraction. We will test whether teneurins also mediate cell-cell interaction in neural circuit assembly in the mouse brain using a combination of MADM analysis, conditional knockout, virus-mediated misexpresssion, and in vitro assays.
Many brain disorders result from disruption of genes that regulate cell-cell communication during neural circuit assembly. Some of the proteins we study are directly related to human brain disorders including intellectual disability and bipolar disorders. Studying how these molecules work will contribute to our understanding of the pathogenesis of these brain disorders.
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