Mitochondrial Morphogenesis, Dendrite Development, and Synapse Formation in Cerebellum Require both Bcl-w and the Glutamate Receptor δ2

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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. A neuron cell is composed of cell body, axons, and dendrites. Dendritic spines on dendrites form synapses with axons of other neurons, establishing communication between neuron cells. Dendrite development and synapse formation are therefore important for neuronal function. Although many genes have been previously identified as affecting the development of dendrites and synapses, the apoptosis Bcl-2 family members have not yet been shown to regulate these processes. In this study, a Bcl-2 family survival member, Bcl-w, was found not to affect cell death, but to be required for synapse formation and motor learning in mouse cerebellum. Bcl-w also appears to control dendrite development as double null mutant mice of Bcl-w and the glutamate receptor δ2 (Grid2) have severe defects in Purkinje cell dendrites, spines, and synapses. In addition, Bcl-w and Grid2 act synergistically to promote what is likely to be mitochondrial fission in Purkinje cells. Neither the survival members of the Bcl-2 family nor the excitatory receptors have been demonstrated previously to regulate mitochondrial morphogenesis in brain. 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.