Mitochondrial morphogenesis, dendrite development, and synapse formation in cerebellum require both Bcl-w and the glutamate receptor delta2.
Mitochondrial morphogenesis, dendrite development, and synapse formation in cerebellum require both Bcl-w and the glutamate receptor delta2.
复制标题
DOI：
10.1371/journal.pgen.1000097
复制
发表时间：
2008-06-13
期刊：
影响因子：
4.5
通讯作者：
Shio H
中科院分区：
文献类型：
--
作者：
Liu QA;Shio H
谷氨酸受体δ2(GRID2)是浦肯野细胞特异性表达的兴奋性受体，是浦肯野细胞突触形成所必需的。最近发表的一项结果以及我们自己的发现表明，Bcl-w可以与自噬蛋白Beclin1物理上相互作用，而Beclin1又被证明与GRID2的胞内结构域和适配蛋白nPIST形成蛋白质复合体。这表明，Bclw和GRID2可能在基因上相互作用，调节线粒体、自噬和神经元功能。在这项研究中，我们通过对Bclw和GRID2蛋白的单突变和双突变小鼠的分析，结合组织学和行为学测试，研究了这两种蛋白的遗传相互作用。研究发现，Bclw不控制小鼠脑内的细胞数量，但促进浦肯野细胞树突中的线粒体分裂，是小脑突触形成和运动学习所必需的，GRID2具有类似的表型。携带这两种基因双重突变的小鼠具有协同效应，包括浦肯野细胞树突中的超长线粒体，以及浦肯野细胞树突、棘突和突触的强烈异常，以及严重的共济失调行为。未发现bclw和GRID2突变影响浦肯野细胞生存所需的基础自噬，从而导致这些表型。我们的结果表明，Bclw和GRID2是调控线粒体形态发生和控制浦肯野细胞树突发育和突触形成的两个关键蛋白。我们认为，神经元生长过程中线粒体的分裂对树突的发育和突触的形成可能是至关重要的，并且它可以受到包括Bcl2和谷氨酸受体家族成员在内的多个途径的协调调节。神经元细胞由胞体、轴突和树突组成。树突上的树突与其他神经元的轴突形成突触，在神经细胞之间建立联系。因此，树突的发育和突触的形成对神经元的功能非常重要。虽然先前已发现许多基因影响树突和突触的发育，但尚未发现凋亡的Bcl2家族成员调节这些过程。本研究发现，Bcl2家族的存活成员Bclw不影响细胞死亡，但对小鼠小脑突触的形成和运动学习是必需的。Bclw似乎也控制着树突的发育，因为bclw和谷氨酸受体δ2(GRID2)的双零突变小鼠在浦肯野细胞的树突、棘突和突触上存在严重的缺陷。此外，Bclw和GRID2协同作用促进浦肯野细胞中可能发生的线粒体分裂。无论是Bcl2家族的存活成员，还是兴奋性受体，都没有被证明调控脑内线粒体的形态发生。我们得出结论，神经元树突的发育和突触的形成可能需要线粒体的分裂，而线粒体分裂可以由两条关键的途径控制，包括Bclw和GRID2。
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.
登录
查看更多内容
影响因子：
64.8
作者：
Karbowski, Mariusz;Norris, Kristi L.;Youle, Richard J.
通讯作者：
Youle, Richard J.
影响因子：
4
作者：
Benard, Giovanni;Bellance, Nadege;Rossignol, Rodrigue
通讯作者：
Rossignol, Rodrigue
影响因子：
1.7
作者：
HIRANO, T;KASONO, K;MISHINA, M
通讯作者：
MISHINA, M
DOI：
10.1083/jcb.200309082
发表时间：
2004-02-16
期刊：
The Journal of cell biology
影响因子：
--
作者：
Karbowski M;Arnoult D;Chen H;Chan DC;Smith CL;Youle RJ
通讯作者：
Youle RJ
影响因子：
64.8
作者：
Komatsu, Masaaki;Waguri, Satoshi;Tanaka, Keiji
通讯作者：
Tanaka, Keiji