During development, precise temporal and spatial gradients are responsible for
guiding axons to their appropriate targets. Within the developing ventral
midbrain (VM) the cues that guide dopaminergic (DA) axons to their forebrain
targets remain to be fully elucidated. Wnts are morphogens that have been
identified as axon guidance molecules. Several Wnts are expressed in the VM
where they regulate the birth of DA neurons. Here, we describe that a precise
temporo-spatial expression of Wnt5a accompanies the development of nigrostriatal
projections by VM DA neurons. In mice at E11.5,
expressed in the VM where it was found to promote DA neurite and axonal growth
in VM primary cultures. By E14.5, when DA axons are approaching their striatal
target, Wnt5a causes DA neurite retraction in primary cultures. Co-culture of VM
explants with Wnt5a-overexpressing cell aggregates revealed that Wnt5a is
capable of repelling DA neurites. Antagonism experiments revealed that the
effects of Wnt5a are mediated by the Frizzled receptors and by the small GTPase,
Rac1 (a component of the non-canonical Wnt planar cell polarity pathway).
Moreover, the effects were specific as they could be blocked by Wnt5a antibody,
sFRPs and RYK-Fc. The importance of Wnt5a in DA axon morphogenesis was further
fasciculation of the medial forebrain bundle (MFB) as well as the density of DA
neurites in the MFB and striatal terminals were disrupted. Thus, our results
identify a novel role of Wnt5a in DA axon growth and guidance.
Publisher: Public Library of Science
Date Published: 31-March-2011
Author(s): Blakely B., Bye C., Fernando C., Horne M., Macheda M., Stacker S., Arenas E., Parish C.