PT - JOURNAL ARTICLE AU - Tseng Kuan-Yin AU - Tatiana Danilova AU - Andrii Domanskyi AU - Mart Saarma AU - Maria Lindahl AU - Mikko Airavaara TI - MANF Is Essential for Neurite Extension and Neuronal Migration in the Developing Cortex AID - 10.1523/ENEURO.0214-17.2017 DP - 2017 Sep 11 TA - eneuro PG - ENEURO.0214-17.2017 4099 - http://www.eneuro.org/content/early/2017/09/11/ENEURO.0214-17.2017.short 4100 - http://www.eneuro.org/content/early/2017/09/11/ENEURO.0214-17.2017.full AB - Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum resident protein with neuroprotective effects. Previous studies have shown that MANF expression is altered in the developing rodent cortex in a spatiotemporal manner. However, the role of MANF in mammalian neurogenesis is not known. The aim of this study was to determine the role of MANF in NSC proliferation, differentiation, and cerebral cortex development. We found that MANF is highly expressed in neural lineage cells, including neural stem cells (NSCs) in the developing brain. We discovered that MANF-deficient NSCs in culture are viable and show no defect in proliferation. However, MANF-deficient cells have deficits in neurite extension upon neuronal differentiation. In vivo, MANF removal leads to slower neuronal migration and impaired neurite outgrowth. In vitro, mechanistic studies indicate that impaired neurite growth is preceded by reduced de novo protein synthesis and constitutively activated unfolded protein response pathways. This study is the first to demonstrate that MANF is a novel and critical regulator of neurite growth and neuronal migration in mammalian cortical development.Significance Statement MANF is a neuroprotective protein, and its expression is high in the developing cortex. However, its role in mammalian neurogenesis is unknown. Here we show that MANF is highly expressed in neural lineage cells, including neural stem cells of the subventricular zone in the developing mouse brain. Unlike other neurotrophic factors, removal of MANF does not alter stem cell proliferation. However, removal of MANF disrupts neurite growth and migration of developing neurons into the cortex. Data in the current manuscript suggests that endogenous MANF is involved in neurite extension, as removal of MANF in NSCs leads to reduced de novo protein synthesis and activated unfolded protein response (UPR) on differentiation.