MANF Is Essential for Neurite Extension and Neuronal Migration in the Developing Cortex

eNeuro. 2017 Sep 29;4(5):ENEURO.0214-17.2017. doi: 10.1523/ENEURO.0214-17.2017. eCollection Sep-Oct 2017.


Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER) 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 neural stem cell (NSC) proliferation, differentiation, and cerebral cortex development. We found that MANF is highly expressed in neural lineage cells, including 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 (UPR) 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.

Keywords: ER stress; MANF; UPR; cerebral dopamine neurotrophic factor; neurotrophic factor.

Publication types

  • Video-Audio Media
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / physiology
  • Cell Movement / physiology*
  • Cell Proliferation / physiology
  • Cell Survival / physiology
  • Cells, Cultured
  • Cerebral Cortex / anatomy & histology
  • Cerebral Cortex / growth & development*
  • Cerebral Cortex / metabolism
  • Mice, Knockout
  • Nerve Growth Factors / genetics
  • Nerve Growth Factors / metabolism*
  • Neural Stem Cells / cytology
  • Neural Stem Cells / metabolism*
  • Neurogenesis / physiology
  • Neuronal Outgrowth / physiology*
  • Neurons / cytology
  • Neurons / metabolism*
  • Organ Size
  • Unfolded Protein Response / physiology


  • MANF protein, mouse
  • Nerve Growth Factors