Elucidating the Dendritic Transport of C1qtnf4 mRNA and the Function of Its Encoded Protein CTRP4 in Dendritic Arborization and Synapse Formation of Neuron

Description

Neuron is distinct from other cell types by the formation of long and elaborate neuronal extensions called axon and dendrite. As a result, the large volume of a neuron requires huge amount of newly synthesized proteins, which renders mRNA translation in the cell body alone insufficient to support the demand. Furthermore, the transport of newly-synthesized proteins from the cell body is too slow to accommodate the rapid changes in protein composition at distal sites that are hundreds of micrometers apart. To circumvent these problems, certain mRNAs and translation machineries are present in axons and dendrites that allow the rapid synthesis of proteins distal from cell body. This “local” protein synthesis is essential for proper brain development and adult brain function such as memory formation. A pre-requisite for local protein synthesis is the transport of selective mRNAs over long distances. While over 2,000 different mRNAs can be present in axons and dendrites, one key question remains unresolved: are different mRNAs transported selectively to distinct compartments in these neuronal extensions? Our unpublished transcriptomic study has identified mRNAs enriched at neuronal connections (the synapses), which supports the notion of differential RNA localization and provides the candidates to explore the spatial heterogeneity of RNA transport in neuron. One novel synaptic mRNA identified by us is C1qtnf4. It exhibits unusual preferential subcellular localization at the branch points of dendrites and near dendritic spines, which represent the sites of neurotransmission between neurons. Interestingly, reduction of the amount of C1qtnf4 mRNA has been reported in the brain of schizophrenia patients and animal models, yet the function of this gene in the brain is poorly understood. C1qtnf4 encodes the secreted protein CTRP4. Our pilot experiments indicate that over-expression of CTRP4 enhances the dendritic growth and branching of hippocampal neurons, while depletion of CTRP4 causes fewer dendritic spines. We therefore hypothesize CTRP4 as a novel key player in the regulation of dendrite development and synapse formation upon local translation and secretion at specialized dendritic compartments. In this proposal we will employ multiple imaging approaches to investigate the specific movement and localization of the C1qtnf4 mRNA in dendrite, as well as to visualize where CTRP4 translation and secretion occur at the subcellular level. We will further determine the neuronal functions of CTRP4 in both cultured hippocampal neurons and in the brain in vivo, which might shed new lights into the potential link between alteration of CTRP4 expression and neurodevelopmental disorder.