Laminin α2 controls mouse and human stem cell behaviour during midbrain dopaminergic neuron development

Abstract

The development of the central nervous system requires the coordination of proliferation and differentiation of neural stem cells. Here, we show that laminin alpha 2 (lm-α2) is a component of the midbrain dopaminergic (mDA) progenitor niche in the ventral midbrain (VM) and identify a concentration-dependent role for lm211 in regulating mDA progenitor proliferation and survival via distinct set of receptors. At high-concentrations, lm211 rich environments maintain mDA progenitors in a proliferative state via integrins α6β1 and α7β1. Whereas low concentrations of lm211 support mDA lineage survival via dystroglycan receptors. We confirmed our findings in vivo where, in the absence of lm-α2, the VM was smaller, with increased apoptosis, and the progenitor pool depleted through premature differentiation resulting in fewer mDA neurons. In examining mDA neuron subtype composition we found a reduction in later-born mDA neurons of the ventral tegmental area, which control a range of cognitive behaviours. Our results identify a novel role for lm in neural development and provide a possible mechanism for autism-like behaviours and brainstem hypoplasia seen in some patients with mutations of the human lm-α2 gene.