Nhsl1b regulates mesodermal cell migration by controlling protrusion dynamics during zebrafish gastrulation

Cell migrations are crucial for embryonic development, wound healing, the immune response, as well as for cancer progression. In most cells, the RAC1/Arp2/3/WAVE signalling pathway induces branched actin polymerisation, which protrudes the membrane and allows migration. Fine-tuning the activity of the RAC1/Arp2/3/WAVE complex modulates protrusion lifetime and migration persistence. Recently, NHSL1, a novel interactor in this complex has been identified as a negative regulator of cell migration in vitro. We here analysed its function in vivo, during zebrafish gastrulation, as nhsl1b is specifically expressed in migrating mesodermal cells. Loss and gain of function experiments revealed that nhsl1b is required for the proper migration of the mesoderm, controlling cell speed and migration persistence. Consistent with a role in regulating actin dynamics, Nhsl1b localises to the tip of actin-rich protrusions. However, in contrast to the in vitro situation, it appears to be a positive regulator of migration, with its loss of function reducing the length and lifetime of protrusions, whereas overexpression has the opposite effect. These results reveal that the effects of actin modulators depend on the cellular context, and highlight the importance of analysing their function in physiological contexts