Cantu, J.A., Flowers, G.P., and Topczewski, J. (2013) Notum homolog plays a novel role in primary motor innervation. The Journal of neuroscience : the official journal of the Society for Neuroscience. 33(5):2177-2187.
To form complex neuronal networks, growth cones use intermediate targets as guideposts on the path to more distant targets.
In the developing zebrafish (Danio rerio), the muscle pioneers (MPs) are intermediate targets for primary motor neurons (PMNs) that innervate the trunk musculature.
The mechanisms regulating PMN axon guidance at the MPs are not fully understood. We have identified a new member of the Notum
family in zebrafish, Notum 2, which is expressed exclusively in the MPs during primary motor innervation. While homologs of
Notum, including zebrafish Notum 1a, negatively regulate the Wnt/β-catenin signaling pathway, we discovered a novel function
of Notum 2 in regulating motor axon guidance. Knockdown of Notum 2 resulted in a failure of caudal primary (CaP) axons to
migrate beyond the MPs, despite the proper specification of the intermediate target. In contrast, mosaic Notum 2 overexpression
induced branching of PMN axons. This effect is specific to Notum 2, as overexpression of Notum 1a does not affect PMN axon
trajectory. Ectopic expression of Notum 2 by cells contacting the growing CaP axon induced the highest frequency of branching,
suggesting that localized Notum 2 expression affects axon behavior. We propose a model where Notum 2 expression at the MPs
provides a cue to release CaP motor axons from their intermediate targets, allowing growth cones to proceed to secondary targets
in the ventral muscle. This work demonstrates an unexpected role for a Notum homolog in regulating growth cone migration,
separate from the well established functions of other Notum homologs in Wnt signaling.