During development of the central nervous system trophic, together with genetic cues, dictate the balance between cellular proliferation and differentiation. Additional intrinsic and extrinsic signals regulate the connectivity of newly born neurons. While a number of regulators in ventral midbrain (VM) dopaminergic (DA) neurogenesis and axon guidance are known, we identify novel roles for the secreted glycoprotein, Wnt7a, in this context.
We demonstrate temporal and spatial expression of Wnt7a indicative of neurogenesis and axonal growth and guidance roles. We show that early expression within the VM regulates NSC proliferation, and thereby dictates the number of intermediate Nurr1 precursors and DA neurons. Additionally, Wnt7a expression promotes the survival of VM neurons, and during early development of the DA pathway, promotes axonal elongation and repels DA neurites out of the midbrain. Later, Wnt7a expression in the thalamus and hypothalamus ensure appropriate trajectory of DA axons en route to their forebrain targets. We show that the effects of Wnt7a in VM development are mediated, at least in part, by the β-catenin/canonical pathways. The timely addition of Wnt7a to mouse embryonic stem cell cultures resulted in significant increase in DA progenitors, DA neurons and elongation of DA neurites. Together, our findings identify Wnt7a as a new regulator of VM DA development. This knowledge could be exploited to increase the yield and connectivity of DA neurons derived from pluripotent stem cell sources for future drug development and cell replacement therapy in Parkinson’s disease.