IPLS Seminar: Prof. Ronen Zaidel-Bar (Tel Aviv University)

Abstract: Gonad development in C. elegans serves as a model for understanding organogenesis and cell migration. While many of the genes involved have been discovered, the cellular and mechanobiological aspects underlying gonad elongation and turning remained poorly understood. Traditionally, it has been assumed that the somatic distal tip cell (DTC) actively leads gonad elongation, with germ cells following.

We used live-imaging, laser ablations, DTC-specific genetic manipulations, and a qualitative physical model, to show that the gonad does not elongates by a pulling force from the leader cell, but rather due to a pushing force generated by the proliferating germ cells, which are confined by a basement membrane behind the DTC. Local release of matrix-degrading metalloproteases by the DTC determines the direction of gonad elongation. Moreover, we identified the mechanism of gonad turning: the DTC concentrates integrin-mediated cell-matrix adhesions on one side and that this temporally controlled asymmetric adhesion generates a bending moment. Genetic perturbations that interfere with adhesion polarity lead to turning defects.

A key feature of DTC migration is the forward positioning of its nucleus. We identified that the KASH domain protein UNC-83 links the nucleus to kinesin-1, moving it along a polarized, acentrosomal microtubule network to counter frictional forces that would otherwise push the nucleus backward. Remarkably, disrupting nuclear positioning alone does not impair morphogenesis, but when combined with reduced actomyosin contractility, the DTC splits, causing gonad bifurcation. Long-term imaging showed that the lagging nucleus stretched the DTC, eventually leading it to fragment into a nucleated cell and an enucleated cytoplast, each forming an independent gonadal arm.

Our findings offer a novel framework to understand normal tissue morphogenesis, and possibly cancer metastasis, in cases where cells are confined by a basement membrane and perform directed invasion.

Host: Guillaume Charras (g.charras@ucl.ac.uk)