Netrins and Wnts Function Redundantly to Regulate Antero-Posterior and Dorso-Ventral Guidance in C. elegans

Abstract

Guided migrations of cells and developing axons along the dorso-ventral (D/V) and antero-posterior (A/P) body axes govern tissue patterning and neuronal connections. In C. elegans, as in vertebrates, D/V and A/P graded distributions of UNC-6/Netrin and Wnts, respectively, provide instructive polarity information to guide cells and axons migrating along these axes. By means of a comprehensive genetic analysis, we found that simultaneous loss of Wnt and Netrin signaling components reveals previously unknown and unexpected redundant roles for Wnt and Netrin signaling pathways in both D/V and A/P guidance of migrating cells and axons in C. elegans, as well as in processes essential for organ function and viability. Thus, in addition to providing polarity information for migration along the axis of their gradation, Wnts and Netrin are each able to guide migrations orthogonal to the axis of their gradation. Netrin signaling not only functions redundantly with some Wnts, but also counterbalances the effects of others to guide A/P migrations, while the involvement of Wnt signaling in D/V guidance identifies Wnt signaling as one of the long sought mechanisms that functions in parallel to Netrin signaling to promote D/V guidance of cells and axons. These findings provide new avenues for deciphering how A/P and D/V guidance signals are integrated within the cell to establish polarity in multiple biological processes, and implicate broader roles for Netrin and Wnt signaling - roles that are currently masked due to prevalent redundancy.

Author Summary

While ample information was gathered in past decades on identifying guidance cues and their downstream mediators, very little is known about how the information from multiple extracellular cues is integrated within the cell to generate normal patterning. Netrin and Wnt signaling pathways are both critical to multiple developmental processes and play key roles in normal development as well as in malignancies. The UNC-6/Netrin guidance cue has a conserved role in guiding cell and growth cone migrations along the dorso-ventral axis, whereas Wnts are critical for determining polarity and guidance along the antero-posterior axis. In this study we show that these two signaling pathways function redundantly in both antero-posterior and dorso-ventral guidance as well as in processes essential for viability. Furthermore, we demonstrate that a fine balance between Wnt and Netrin signaling pathways is critical for proper polarity establishment and identify Wnt signaling as one of the long sought mechanisms that signal in parallel to Netrin to promote dorso-ventral guidance of cells and axons in Caenorhabditis elegans. These findings pave the way to unraveling the broader roles of Wnt and Netrin signaling pathways and provide a conceptually novel view of how antero-posterior and dorso-ventral guidance mechanisms are orchestrated.