During tissue morphogenesis, cells need to be promiscuous, rapidly going through cycles of adhesion and de-adhesion with different cells. The adhesion protein E-cadherin has previously been shown to be required for proper migration of progenitor cells during zebrafish gastrulation. A study in Dev. Cell now suggests that Wnt11, also known to be important for this process, regulates cell cohesion and movement at least in part by triggering endocytosis of E-cadherin.

During gastrulation prechordal plate progenitors migrate from the germ ring towards the animal pole. By tracking the movement of these cells in fish mutant for Wnt11, Ulrich et al. demonstrate that Wnt11 regulates the speed and direction of cell migration. Not only do mutant cells move less rapidly than wild-type cells, but they are also unable to move in a straight line within a cohesive tissue, suggesting that Wnt11 might regulate cell-cell adhesion.

Given the well-established role of E-cadherin in cell-cell adhesion, the authors examined whether disruptions to E-cadherin function underlie the defects observed in Wnt11 mutants. They found that when Wnt11 is lost, E-cadherin is mainly localized on the plasma membrane of germ ring cells. However, when they re-introduced Wnt11 expression at the onset of gastrulation, E-cadherin relocalizes to discrete cytoplasmic puncta.

These results raised the possibility that Wnt11 could be triggering E-cadherin endocytosis and led the authors to analyse the localization of a key regulator of endocytosis, Rab-5c. Supporting this idea, E-cadherin puncta colocalized with Rab-5c in the cytoplasm in wild-type embryos and expression of active Rab-5c in Wnt11 mutants was sufficient to induce E-cadherin relocalization to the cytoplasm. More importantly, expression of Rab-5c restored the prechordal plate movements in Wnt11 mutants, suggesting that Rab-5c mediates Wnt-induced endocytosis and cell motility.

Finally, Ulrich et al. examined the adhesion of Wnt11 mutant cells to E-cadherin substrates using atomic force microscopy. In agreement with previous results, they found that the force required to separate wild-type cells from the substrate is less than that required to separate cells lacking Wnt11 or Rab5c. So it seems that Wnt11 and Rab-5c are required for proper E-cadherin adhesion.

In summary, this paper suggests that Wnt11 regulates the dynamics of E-cadherin adhesion during gastrulation by promoting endocytosis. However, cadherins are not the only Wnt11 target in this process: a recent study from the same laboratory shows that Wnt11 also modulates integrin adhesion. It will be interesting to determine which adhesion targets are most important for Wnt11 function in gastrulation, and whether Wnt11 affects endocytosis in both cases.

Author: Monica Hoyos-Flight