Abstract
Bcl-w belongs to the prosurvival group of the Bcl-2 family, while the glutamate receptor δ2 (Grid2) is an excitatory receptor that is specifically expressed in Purkinje cells, and required for Purkinje cell synapse formation. A recently published result as well as our own findings have shown that Bcl-w can physically interact with an autophagy protein, Beclin1, which in turn has been shown previously to form a protein complex with the intracellular domain of Grid2 and an adaptor protein, nPIST. This suggests that Bcl-w and Grid2 might interact genetically to regulate mitochondria, autophagy, and neuronal function. In this study, we investigated this genetic interaction of Bcl-w and Grid2 through analysis of single and double mutant mice of these two proteins using a combination of histological and behavior tests. It was found that Bcl-w does not control the cell number in mouse brain, but promotes what is likely to be the mitochondrial fission in Purkinje cell dendrites, and is required for synapse formation and motor learning in cerebellum, and that Grid2 has similar phenotypes. Mice carrying the double mutations of these two genes had synergistic effects including extremely long mitochondria in Purkinje cell dendrites, and strongly aberrant Purkinje cell dendrites, spines, and synapses, and severely ataxic behavior. Bcl-w and Grid2 mutations were not found to influence the basal autophagy that is required for Purkinje cell survival, thus resulting in these phenotypes. Our results demonstrate that Bcl-w and Grid2 are two critical proteins acting in distinct pathways to regulate mitochondrial morphogenesis and control Purkinje cell dendrite development and synapse formation. We propose that the mitochondrial fission occurring during neuronal growth might be critically important for dendrite development and synapse formation, and that it can be regulated coordinately by multiple pathways including Bcl-2 and glutamate receptor family members.
Highlights
Mitochondria have been shown to undergo morphological changes in many neurodegenerative and psychiatric diseases, suggesting their vital role in maintaining the normal function of neuron cells
We conclude that neuronal dendrite development and synapse formation require perhaps mitochondrial fission that can be controlled by two critical pathways including Bcl-w and Grid2
We show that the survival member of the Bcl-2 family member, Bcl-w does not control the cell number in brain, but promotes what is likely to be the mitochondrial fission in Purkinje cell dendrites, and is required for the Purkinje cells/parallel fibers synapses and motor learning
Summary
Mitochondria have been shown to undergo morphological changes in many neurodegenerative and psychiatric diseases, suggesting their vital role in maintaining the normal function of neuron cells. Mitochondria are dynamic organelles that can undergo fission, fusion, branching, and change in subcellular distribution [1,2,3], resulting in the exchange of their genetic materials, alteration of their shape, and increase or decrease of their number [1,2,3]. This dynamic nature of mitochondria is critically important for energy generation, calcium buffering, and control of apoptosis. Several proteins have been identified in a variety of species to mediate mitochondrial fission or fusion process [2,3], little is known about the signaling molecules that activate these processes
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