Poster Presentation 6th Australian Health and Medical Research Congress 2012

Diverse roles for Wnt7a in ventral midbrain neurogenesis and dopaminergic axon morphogenesis (#402)

Chathurini V Fernando 1 , Brette D Blakely 1 2 , Christopher R Bye 1 , Jonathan C Niclis 1 , Brad J Turner 1 , Julianna Kele 3 , Jan Stenman 3 , Ernest Arenas 4 , Clare L Parish 1 2
  1. Florey Institute of Neuroscience and Mental Health, Melbourne University, Melbourne, Australia
  2. Centre for Neurosciences, Melbourne University, Melbourne, Australia
  3. Ludwig Institute for Cancer Research, Karolinska Institute, Stockholm, Sweden
  4. Department of Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden

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 and axonal growth and guidance.  In primary VM cultures and Wnt7a deficient mice, we show that early expression within the VM is important for the regulating VM neural stem cell proliferation, thereby dictating the number of Nurr1 precursors and DA neurons. Additionally Wnt7a promotes the survival of VM neurons.  During early development of the DA pathways, Wnt7a promotes axonal elongation and repel DA neurites out of the midbrain. Later, Wnt7a expression in the VM midline suggests a role in preventing axonal crossing whilst 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, our findings identify Wnt7a as a new regulator of the VM stem cell population, neurogenesis and DA axon growth and guidance.