Cell migration is a critical developmental and physiological phenomenon for embryogenesis, wound healing, tissue repair and remodeling. Cells travel long or short distances to reach their final destination e.g. during embryogenesis cells of different lineages migrate in time and space to form specific tissues or organs at a predetermined location. Likewise, an injured or infected tissue sends out an inflammatory signal which rapidly recruits immune cells for the repair of damaged tissue regaining the tissue integrity. Defects in cell migration have severe consequences like birth defects, vascular disorders, neurological diseases etc. In vivo, cells move around in a three-dimension (3D) microenvironment interacting with extracellular matrix, body fluids, growth

factors, as well as other cells and tissues. 3D cell culture studies have identified several modes of cell migration such as mesenchymal, amoeboid, lobopodial, sling-shot and many others regulated by key factors like actomyosin contractility, cell-ECM adhesion and confinement (Petrie, R. J., & Yamada, K. M. (2012) J Cell Sci, 125(24), 5917-5926; Agarwal, P., & Zaidel-Bar, R. (2019) Essays in biochemistry, 63(5), 497-508; Yamada, K. M., & Sixt, M. (2019) Nature Reviews Molecular Cell Biology, 1-15). Since in vitro 3D cell cultures do not recapitulate the complex and diverse tissue environment that cells encounter during migration in vivo, the physiological relevance of these different modes of 3D cell migration remains ambiguous. Hence, we need in vivo models to validate the in vitro mechanisms or identify and understand undiscovered mechanistic details of 3D cell migration.

Morphogenesis of the nematode Caenorhabditis elegans gonad depends upon the migration of two somatic cells known as distal tip cell (DTCs) and is an excellent model to study 3D cell migration in vivo. The transparent worm body allows visualization and analysis of cell migration using a dissecting microscope. Other advantages of using it as a model for cell migration include its invariant migration pattern, simpler anatomy, and ease of genetic manipulation. The C. elegans hermaphrodite has two U-shaped gonadal arms which form post-embryonically. After hatching, the gonad primordium consists of two somatic precursors – Z1 and Z4 – giving rise to somatic structures (uterus, spermatheca, sheath cells and DTCs) and two germline precursors – Z2 and Z3 – which form the entire germline. The migration trajectory of the two DTCs, present at the two ends of the gonad primordium, determines the final morphology of the mature hermaphrodite gonad (See image below).

DTCs function as leader cells migrating with several follower germ cells in three distinct phases. In the first phase, during larval stage 2 (L2) and early larval stage 3 (L3) the two DTCs move away from each other. The second phase involves a 90-degree turn of DTCs moving from ventral to dorsal surface. Finally, during early L4 stage DTCs make a second 90-degree turn, migrating towards the middle position of the body, ultimately forming two U-shaped gonadal arms.

 

Despite a significant advancement in the identification of molecular signals and the role of basement membrane in DTC migration, the mechanism of DTC migration is still not unclear. Distal tip cell migration is analogous to the phenomena of branching of tubular organs in vertebrates and cancer metastasis. Hence, understanding the molecular and physical aspects of DTC migration might help us to gain insights into organogenesis and invasive tumors.