Niche-derived laminin-511 promotes midbrain dopaminergic neuron survival and differentiation through YAP

Sci Signal. 2017 Aug 22;10(493):eaal4165. doi: 10.1126/scisignal.aal4165.

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder in which the loss of dopaminergic neurons in the midbrain (mDA neurons) causes progressive loss of motor control and function. Using embryonic and mDA neurons, midbrain tissue from mice, and differentiated human neural stem cells, we investigated the mechanisms controlling the survival of mDA neurons. We found that the extracellular matrix protein laminin-511 (LM511) promoted the survival and differentiation of mDA neurons. LM511 bound to integrin α3β1 and activated the transcriptional cofactor YAP. LM511-YAP signaling enhanced cell survival by inducing the expression of the microRNA miR-130a, which suppressed the synthesis of the cell death-associated protein PTEN. In addition, LM511-YAP signaling increased the expression of transcription factors critical for mDA identity, such as LMX1A and PITX3, and prevented the loss of mDA neurons in response to oxidative stress, a finding that warrants further investigation to assess therapeutic potential for PD patients. We propose that by enhancing LM511-YAP signaling, it may be possible to prevent mDA neuron degeneration in PD or enhance the survival of mDA neurons in cell replacement therapies.

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Brain / metabolism*
  • Cell Cycle Proteins
  • Cell Differentiation*
  • Cell Survival
  • Cells, Cultured
  • Dopamine / metabolism
  • Dopaminergic Neurons / cytology*
  • Dopaminergic Neurons / metabolism
  • Embryo, Mammalian / cytology
  • Embryo, Mammalian / metabolism
  • Female
  • Gene Expression Regulation, Developmental
  • Humans
  • Integrin alpha3beta1 / metabolism
  • Laminin / metabolism*
  • Mice
  • MicroRNAs / metabolism
  • Neural Stem Cells / cytology*
  • Neural Stem Cells / metabolism
  • PTEN Phosphohydrolase / metabolism
  • Parkinson Disease / genetics
  • Parkinson Disease / metabolism
  • Parkinson Disease / pathology*
  • Phosphoproteins / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • Integrin alpha3beta1
  • Laminin
  • MIRN130 microRNA, mouse
  • MicroRNAs
  • Phosphoproteins
  • Yap protein, mouse
  • laminin-511, mouse
  • PTEN Phosphohydrolase
  • Pten protein, mouse
  • Dopamine