MGARP regulates mouse neocortical development via mitochondrial positioning.

Neocortical development is an extremely complicated process that critically depends on the proper migration, distribution, and positioning of neural cells. Here, we identified mitochondria-localized glutamic acid-rich protein (MGARP) as a negative regulator of neocortical development. In the developing neocortex, the overexpression of MGARP by in utero electroporation impedes the radial migration of neocortical cells to their final destination. These neocortical cells failed to be normally polarized, leading to shortened axons and compromised axonal bundles. The number of dendrites was also attenuated in cells with MGARP overexpression and was expanded in MGARP-knockdown or knockout cells. Mechanistic studies indicated that overexpression of MGARP caused alterations in the structural integrity, subcellular distribution, and motility of mitochondria. The mitochondria in MGARP-overexpressing cells became "fatty" with a round morphology, and the total number of mitochondria in MGARP-overexpressing cells was also decreased in the cell body and dendrites as well as in the axons. Time lapse studies showed that the ratio of motile mitochondria was remarkably decreased in the axons of MGARP-overexpressing cells. Together, our findings suggest that MGARP negatively mediates neocortical development by regulating mitochondrial distribution and motility in neocortical neurons.