23 March

Should I stop or should I go: how a novel communication mechanism between non-canonical and canonical Wnt signaling controls cell migration

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Researchers from the group of Rik Korswagen discovered a new mechanism of communication between different Wnt signaling pathways. These pathways allow neuroblasts – the precursors of neurons – to know when they have to stop their movement from the location where they were born to the location where they need to end up. The findings provide insight into how Wnt signaling regulates different aspects of cell migration, an important process in development, health and disease. The results will be published in the scientific journal PNAS this week.

During animal development, cells often have to migrate to different locations within the body than the ones where they were born. If they fail to correctly do this, the consequences on the formation of the body can be harmful and potentially fatal. The team of Rik Korswagen has been using the roundworm C. elegans to investigate the genetic mechanisms that regulate the different aspects of cell migration; from how it is triggered to how it stops.

Neuroblasts migrating from their place of birth (0 min) to their final destination (120 min). Credit: Lorenzo Rella, image adapted from Rella et al., PNAS (2021).
Understanding cell migration, one roundworm at a time

For the current study, that was published in PNAS, the researchers looked at migratory neuroblasts – cells that are in the process of becoming neurons – of the roundworms. These cells must migrate to very specific locations in order to correctly form part of the nervous system. In previous work, the Korswagen group showed that sequential activation of different Wnt signaling pathways is responsible for various events during the migration of these cells. The so-called non-canonical Wnt signaling pathways are responsible for making these neuroblasts move, while the canonical Wnt pathway comes into play to control when they stop moving. However, a crucial piece of the puzzle remained uncovered: how do these pathways communicate with each other?

ON- and OFF buttons

Canonical Wnt signaling is widely known to control gene expression. Therefore, the researchers had a hint on how to look for the missing link: a technique called RNA sequencing. They found that, after activation of the canonical Wnt signaling pathway, two genes – EVA-1/EVA1C and RGA-9b/ARHGAP – are responsible for making the cells stop their movement. The discovery of the two genes started to unveil a mechanism through which the different pathways can communicate. RGA-9b/ARHGAP is a Rho GAP, a protein that works as the OFF button for “cellular switches” called Rho family GTPases. Euclides Fernandes Póvoa, one of the first authors on the paper, explains: “If canonical Wnt signaling controls the OFF button of these switches to stop migration, we speculated that non-canonical Wnt signaling must control an “ON” button that activates them.” Subsequent experiments showed that the non-canonical Wnt signaling pathway indeed activates one of these ON buttons – the Rho GEF PIX-1. “We found that these ON and OFF buttons counteract each other’s activity to ensure that the cells stop at the precise location,” says Fernandes Póvoa. 

From roundworms to humans

Canonical and non-canonical Wnt signaling also have opposing roles in vertebrates. For example, the two pathways control the migration of neural crest cells – a family of progenitor cells that form tissues as diverse as cartilage and the melanocytes of the skin – counteract each other’s activity. A similar antagonistic relationship is also observed in some types of cancer, most notably melanoma, a deadly skin cancer. “An exciting possibility is therefore that the communication mechanism that we discovered in C. elegans may also have important implications in understanding vertebrate development and disease,” says Rik Korswagen, leading author of the study.

Publication

Lorenzo Rella, Euclides E. Fernandes Póvoa, Jonas Mars, Annabel L. P. Ebbing, Luc Schoppink, Marco C. Betist, and Hendrik C. Korswagen. A switch from noncanonical to canonical Wnt signaling stops neuroblast migration through a Slt–Robo and RGA-9b/ARHGAP–dependent mechanism. PNAS (2021).

 

 

Rik Korswagen is a group leader at the Hubrecht Institute and professor of Molecular Developmental Genetics at Utrecht University.