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Neurons and axons have polarity which gives them direction in the body. Positioning is fundamental to any organism. All cellular structures must be precisely oriented in order to work accurately.
To better understand how neuron and axon migration work, lead author Naomi Levy-Strumpf, PhD along with principal investigator Joseph Culotti, PhD investigated the netrin and Wnt signaling pathways in the humble worm C. elegans. Caenorhabditis elegans, or C. elegans, is a transparent, non-parasitic roundworm about 1 mm in length that lives in soil. As of 2012, it is the only organism to have its "wiring" completely genetically diagrammed.
Within the cytoplasm of cells, proteins emit signals which either attract or repel other proteins.
Levy-Strumpf and Culotti chose to examine the UNC-6/netrin system as each part of this system was known for its affect on migration. UNC-6/netrin emits an attract signal guiding cell migration along a middle axis (dorso-ventral or D/V). In a human D/V would indicate the path from our back to our belly. Meanwhile, the Wnts protein pathways are critical for determining polarity and guidance along a head to toe axis (antero-posterior or A/P).
The researchers unexpected finding is that UNC-6/netrin and Wnts pathway emit both A/P and D/V signals. This redundant behavior probably functions to increase the reliability of both systems. This is a new concept in how A/P and D/V guidance generates cell migration.
"This redundancy tends to mask the roles of netrin and Wnt signaling in various biological processes. Now that we have identified their redundancy - we have better insight into how these two key signalling pathways contribute in normal development as well as to tumor progression and metastasis."
Naomi Levy-Strumpf, PhD, research associate, Culotti lab, Department of Molecular Genetics, University of Toronto, Ontario, Canada
'In addition to providing polarity information for migration along the axis of their gradation, Wnts and netrin are each able to guide migrations orthogonal [lying at right angles] to the axis of their gradation. These results suggest the existence of novel mechanisms for guiding cell migrations that are different from previously demonstrated mechanisms involving simple attraction toward or repulsion away from a guidance cue."
Joseph Culotti, PhD, principal investigator, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada, Department of Molecular Genetics, University of Toronto, Ontario, Canada
"This is an excellent example of the power of genetic analysis of the worm in neurobiology," says Dr. Jim Woodgett, Director of the Lunenfeld-Tanenbaum. "Now that this pathway interaction has been shown to occur, it'll only be a matter of time for someone to replicate it in mice."
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.
This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding was provided by the Canadian Institutes for Health Research, Canadian Foundation for Innovation, Canada Research Chairs, and Mount Sinai Hospital Foundation.