The precise control of neuronal migration and morphological changes during differentiation is essential for neocortical development. We hypothesized that the transition of progenitors through progressive stages of differentiation involves dynamic changes in levels of mitochondrial reactive oxygen species (mtROS), depending on cell requirements. We found that progenitors had higher levels of mtROS, but that these levels were significantly decreased with differentiation. The Prdm16 gene was identified as a candidate modulator of mtROS using microarray analysis, and was specifically expressed by progenitors in the ventricular zone. However, Prdm16 expression declined during the transition into NeuroD1-positive multipolar cells. Subsequently, repression of Prdm16 expression by NeuroD1 on the periphery of ventricular zone was crucial for appropriate progression of the multipolar phase and was required for normal cellular development. Furthermore, time-lapse imaging experiments revealed abnormal migration and morphological changes in Prdm16-overexpressing and -knockdown cells. Reporter assays and mtROS determinations demonstrated that PGC1α is a major downstream effector of Prdm16 and NeuroD1, and is required for regulation of the multipolar phase and characteristic modes of migration. Taken together, these data suggest that Prdm16 plays an important role in dynamic cellular redox changes in developing neocortex during neural differentiation.

Author contributions

K.M. designed this study and wrote the manuscript; M.I., R.I., H.T., D.K., M.K.-S., C.W., F.M., K.N. and K.M. performed this study and analyzed data; H.I., Y.M. and T.H. generated an antibody. All authors discussed the results and commented on the manuscript.

Funding

This research was supported by Japan Science and Technology Agency, Precursory Research for Embryonic Science and Technology (PRESTO) ‘Development and Function of Neural Networks’ (111832), by a Grant-in-Aid for Scientific Research on Innovative Areas ‘Neurovascular’ from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan (25122718) and by the Takeda Science Foundation.

Data availability

Microarray data have been deposited at ArrayExpress under accession number E-MTAB-5438.

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