During development of the central nervous system, trophic, together with genetic, cues dictate the balance between cellular proliferation and differentiation. Subsequent to the birth of new neurons, additional intrinsic and extrinsic signals regulate the connectivity of these cells. While a number of regulators of ventral midbrain (VM) neurogenesis and dopaminergic (DA) axon guidance are known, we identify a number of novel roles for the secreted glycoprotein, Wnt7a, in this context. We demonstrate a temporal and spatial expression of Wnt7a in the VM, indicative of roles in neurogenesis, differentiation, and axonal growth and guidance. In primary VM cultures, and validated in Wnt7a-deficient mice, we show that the early expression within the VM is important for regulating VM progenitor proliferation, cell cycle progression, and cell survival, thereby dictating the number of midbrain Nurr1 precursors and DA neurons. During early development of the midbrain DA pathways, Wnt7a promotes axonal elongation and repels DA neurites out of the midbrain. Later, Wnt7a expression in the VM midline suggests a role in preventing axonal crossing while expression in regions flanking the medial forebrain bundle (thalamus and hypothalamus) ensured 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. Together, these findings identify Wnt7a as a new regulator of VM neurogenesis and DA axon growth and guidance.
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