The long-term goals of the proposed research are to elucidate the signaling mechanisms regulating neuronal morphogenesis and connectivity in the mammalian brain. The major protein kinase CaMKII predominantly consists of the Alpha and Beta isoforms in the brain. Although CaMKIIBeta functions have been elucidated, the isoform- specific catalytic functions of CaMKIIBeta have remained largely unexplored. Using rigorously controlled knockdown analyses in primary rat neurons and in the rodent cerebellar cortex in vivo, we recently discovered the first unique catalytic function of CaMKIIBeta in the mammalian brain. Remarkably, CaMKIIBeta operates at the centrosome in a CaMKIIAlpha-independent manner to drive dendrite retraction and pruning. In other studies, we found that the TRP channel TRPC5 forms a specific complex with CaMKIIBeta, but not CaMKIIAlpha, and thereby triggers the activation of centrosomal CaMKIIBeta signaling leading to dendrite retraction and pruning in granule neurons and in the cerebellar cortex in vivo. Our findings define a novel TRPC5-regulated centrosomal CaMKIIBeta signaling pathway that controls dendrite patterning in the mammalian brain. Our findings also raise fundamental questions on the molecular basis of TRPC5-regulation of CaMKIIBeta signaling at the centrosome and the mechanisms by which centrosomal CaMKIIBeta regulates dendrite morphogenesis. To address these questions, in structure-function analyses we will test the hypothesis that distinct peptide motifs within TRPC5 and CaMKIIBeta specify the TRPC5/CaMKIIBeta interaction and thereby regulate dendrite patterning in the rodent cerebellar cortex in vivo. Using candidate and innovative unbiased biochemical approaches, we will identify novel substrates of centrosomal CaMKIIBeta and determine their role in the CaMKIIBeta-regulation of dendrite morphogenesis in granule neurons and in the rodent cerebellar cortex in vivo. Finally, in recent exciting studies, we have discovered that proteasomes operate at the centrosome to promote dendrite growth. Based on preliminary data, we will test the hypothesis that centrosomal CaMKIIBeta signaling regulates proteasome activity at the centrosome and thereby controls dendrite morphogenesis. The proposed research represents an important set of experiments that will advance our understanding of the mechanisms that control dendrite patterning and connectivity in the mammalian brain. Since disruption of dendrite connectivity contributes to the pathogenesis of diverse neurological diseases including intellectual disability and autism spectrum disorders, our studies will also advance our understanding of these devastating neurological diseases.
Dendrite morphogenesis represents a fundamental prerequisite step in the establishment of neural circuits in the brain. We propose to identify the key mechanisms and principles that govern dendrite morphogenesis in brain development. Abnormalities of dendrite morphogenesis contribute to the pathogenesis of cognitive disorders including intellectual disability and autism spectrum disorders. Therefore, understanding the mechanisms that control dendrite morphogenesis is not only essential for a better understanding of brain development but also for insights into a whole host of brain disorders.
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| Valnegri, Pamela; Puram, Sidharth V; Bonni, Azad (2015) Regulation of dendrite morphogenesis by extrinsic cues. Trends Neurosci 38:439-47 |
| Ito, H; Shiwaku, H; Yoshida, C et al. (2015) In utero gene therapy rescues microcephaly caused by Pqbp1-hypofunction in neural stem progenitor cells. Mol Psychiatry 20:459-71 |
