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

Medical Department, Brookhaven National Laboratory, Upton, New York, USA.
PLoS Genetics (Impact Factor: 7.53). 07/2008; 4(6):e1000097. DOI: 10.1371/journal.pgen.1000097
Source: PubMed


Bcl-w belongs to the prosurvival group of the Bcl-2 family, while the glutamate receptor delta2 (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.

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    • "It is likely that neurotransmitters and neurotrophic factors control mitochondrial dynamics because of their influences on neuronal energy metabolism, calcium homeostasis and dendritic and axonal motility. Indeed, a recent study showed that cerebellar Purkinje cells in mice deficient in the glutamate receptor Grid2 exhibit extremely long mitochondria, abnormal spines and synapses, and severe ataxia, providing evidence that glutamate receptor-mediated signalling affects mitochondrial fission and/or fusion (Liu and Shio, 2008). Further studies aimed at clarifing the effects of neurotransmitters and neurotrophic factors on the molecular machineries that regulate mitochondrial fission, fusion and movement within neurons, will expand the knowledge of the integration of mitochondrial motility with neuronal functional and structural dynamics. "
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    • "BCL2-like 11 protein is encoded by a gene in the BCL-2 protein family, which play important roles in the regulation of neuronal and lymphocytic apoptosis. BCL-2 deficiency does not affect neuronal numbers in the cerebellum [35], but this protein has been implicated in hippocampal neuronal protection in a seizure model [36]. BCL-2-deficient mice exhibit relatively normal development of the nervous system, but BCL-2 is important for the postnatal maintenance of specific neuronal subsets, including facial motor neurons and dorsal root ganglia [37]. "
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    • "First, axonal mitochondria are longer in bcl-w −/− than in bcl-w +/+ DRG neurons (Figure 7A and 7B). Similarly, it has previously been reported that mitochondria in Purkinje cell dendrites of bclw −/− mice are elongated (Liu and Shio, 2008). Lack of Bcl-w does not alter expression of proteins critical for mitochondrial fission and fusion (Figure 7E), suggesting that Bcl-w may alter mitochondrial length by direct interactions with components of the fission/fusion machinery, as reported for other Bcl-2 family members (Karbowski et al., 2006; Delivani et al., 2006; Brooks et al., 2007; Bernam, 2009). "
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