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Calcium dysregulation mediates mitochondrial and neurite outgrowth abnormalities in SOD2 deficient embryonic cerebral cortical neurons.

ABSTRACT: Mitochondrial superoxide dismutase 2 (SOD2) is a major antioxidant defense enzyme. Here we provide evidence that SOD2 plays critical roles in maintaining calcium homeostasis in newly generated embryonic cerebral cortical neurons, which is essential for normal mitochondrial function and subcellular distribution, and neurite outgrowth. Primary cortical neurons in cultures established from embryonic day 15 SOD2^+/+ and SOD2^-/- mice appear similar during the first 24?h in culture. During the ensuing two days in culture, SOD2^-/- neurons exhibit a profound reduction of neurite outgrowth and their mitochondria become fragmented and accumulate in the cell body. The structural abnormalities of the mitochondria are associated with reduced levels of phosphorylated (S637) dynamin related protein 1 (Drp1), a major mitochondrial fission-regulating protein, whereas mitochondrial fusion regulating proteins (OPA1 and MFN2) are relatively unaffected. Mitochondrial fission and Drp1 dephosphorylation coincide with impaired mitochondrial Ca²⁺ buffering capacity and an elevation of cytosolic Ca²⁺ levels. Treatment of SOD2^-/- neurons with the Ca²⁺ chelator BAPTA-AM significantly increases levels of phosphorylated Drp1, reduces mitochondrial fragmentation and enables neurite outgrowth.

SUBMITTER: Zhao Q

PROVIDER: S-EPMC6748124 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Calcium dysregulation mediates mitochondrial and neurite outgrowth abnormalities in SOD2 deficient embryonic cerebral cortical neurons.

Zhao Qijin Q Lu Daoyuan D Wang Jing J Liu Beibei B Cheng Heping H Mattson Mark P MP Cheng Aiwu A

Cell death and differentiation 20181102 9

Mitochondrial superoxide dismutase 2 (SOD2) is a major antioxidant defense enzyme. Here we provide evidence that SOD2 plays critical roles in maintaining calcium homeostasis in newly generated embryonic cerebral cortical neurons, which is essential for normal mitochondrial function and subcellular distribution, and neurite outgrowth. Primary cortical neurons in cultures established from embryonic day 15 SOD2<sup>+/+</sup> and SOD2<sup>-/-</sup> mice appear similar during the first 24 h in cultur ...[more]

PMID: 30390091

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Project description:The formation of connections within the mammalian neocortex is highly regulated by both extracellular guidance mechanisms and intrinsic gene expression programs. There are two types of cortical projection neurons (CPNs): those that project locally and interhemispherically and those that project to subcerebral structures such as the thalamus, hindbrain, and spinal cord. The regulation of cortical projection morphologies is not yet fully understood at the molecular level. Here, we report a role for Mllt11 (Myeloid/lymphoid or mixed-lineage leukemia; translocated to chromosome 11/All1 Fused Gene From Chromosome 1q) in the migration and neurite outgrowth of callosal projection neurons during mouse brain formation. We show that Mllt11 expression is exclusive to developing neurons and is enriched in the developing cortical plate (CP) during the formation of the superficial cortical layers. In cultured primary cortical neurons, Mllt11 is detected in varicosities and growth cones as well as the soma. Using conditional loss-of-function and gain-of-function analysis we show that Mllt11 is required for neuritogenesis and proper migration of upper layer CPNs. Loss of Mllt11 in the superficial cortex of male and female neonates leads to a severe reduction in fibers crossing the corpus callosum (CC), a progressive loss in the maintenance of upper layer projection neuron gene expression, and reduced complexity of dendritic arborization. Proteomic analysis revealed that Mllt11 associates with stabilized microtubules, and Mllt11 loss affected microtubule staining in callosal axons. Taken together, our findings support a role for Mllt11 in promoting the formation of mature upper-layer neuron morphologies and connectivity in the cerebral cortex.SIGNIFICANCE STATEMENT The regulation of cortical projection neuron (CPN) morphologies is an area of active investigation since the time of Cajal. Yet the molecular mechanisms of how the complex dendritic and axonal morphologies of projection neurons are formed remains incompletely understood. Although conditional mutagenesis analysis in the mouse, coupled with overexpression assays in the developing fetal brain, we show that a novel protein called Mllt11 is sufficient and necessary to regulate the dendritic and axonal characteristics of callosal projection neurons in the developing mammalian neocortex. Furthermore, we show that Mllt11 interacts with microtubules, likely accounting for its role in neuritogenesis.

Dataset Information

Calcium dysregulation mediates mitochondrial and neurite outgrowth abnormalities in SOD2 deficient embryonic cerebral cortical neurons.

Publications

Calcium dysregulation mediates mitochondrial and neurite outgrowth abnormalities in SOD2 deficient embryonic cerebral cortical neurons.

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