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

The authors investigated the mechanisms controlling the survival of mDA neurons using embryonic and mDA neurons, midbrain tissue from mice, and differentiated human neural stem cells. The work identifies laminin511-YAP as a key pathway by which niche signals control the survival and differentiation of mDA neurons. Laminin alpha-5 is present in the extracellular matrix surrounding mDA neurons and indeed, the authors found laminin-511 promoted the survival and differentiation of mDA neurons via a novel pathway involving YAP, miR-130a, and PTEN. Laminin-511 bound to integrin a3b1 and activated the transcriptional cofactor YAP. Laminin511-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, laminin511-YAP signaling increased the expression of transcription factors critical for mDA identities, 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 the therapeutic potential for PD patients. The authors propose that by enhancing laminin511-YAP signaling, it may be possible to prevent mDA neuron degeneration in PD or enhance the survival of mDA neurons in cell replacement therapies.