Organogenesis requires the proper production of diverse cell types and their positioning/migration. However, the coordination of these processes during development remains poorly understood. The gonad in C. elegans exhibits a mirror-symmetric structure guided by the migration of distal tip cells (DTCs), which result from asymmetric divisions of somatic gonadal precursors (SGPs; Z1 and Z4). We found that the polarity of Z1 and Z4, which possess mirror-symmetric orientation, is controlled by the redundant functions of the LIN-17/Frizzled receptor and three Wnt proteins (CWN-1, CWN-2, and EGL-20) with distinct functions. In lin-17 mutants, CWN-2 promotes normal polarity in both Z1 and Z4, while CWN-1 promotes reverse and normal polarity in Z1 and Z4, respectively. In contrast, EGL-20 inhibits the polarization of both Z1 and Z4. In lin-17 egl-20 cwn-2 triple mutants with a polarity reversal of Z1, DTCs from Z1 frequently miss-migrate to the posterior side. Our further analysis demonstrates that the mis-positioning of DTCs in the gonad due to the polarity reversal of Z1 leads to mis-migration. Similar mis-migration was also observed in cki-1(RNAi) animals producing ectopic DTCs. These results highlight the role of Wnt signaling in coordinating the production and migration of DTCs to establish a mirror-symmetric organ.
Keywords: C. elegans; Wnt; cell migration; cell polarity; developmental biology; organogenesis.
In humans and other animals, cells are organized into tissues and organs that each perform distinct roles in the body. Some organs and tissues have a mirror-symmetric structure, meaning they are divided into two halves that are exact reflections of one another. However, it is not fully understood how these types of structures form during development. The formation of mirror-symmetric structures often relies on cell polarity, which is when the components of a cell – such as its structure, internal contents and functional regions – are unevenly distributed. In the nematode worm C. elegans, for example, their mirror-symmetric gonads (or sex organs) are formed by two polarized cells called Z1 and Z4. Both Z1 and Z4 divide asymmetrically to produce two daughter cells with distinct concentrations of a particular transcription factor. For Z1, the daughter cell facing the anterior of the gonad has lower levels of the transcription factor than the posterior daughter cell, while the two cells generated by Z4 have the opposing mirror asymmetry. This polarity drives the production of two distal tip cells – one produced by the anterior daughter cell of Z1 and the other by the posterior daughter cell of Z4 – which migrate to opposite ends of the gonad. A cell signaling pathway known as Wnt is crucial for establishing cell polarity in many species. However, a previous study found that C. elegans could still develop healthy gonads even when all five ligand proteins that activate the Wnt pathway were mutated. Here, So et al. reveal that these mutations can impact polarity, but only when LIN-17, the receptor for the Wnt ligands, is also mutated. Further experiments showed that LIN-17 can independently regulate cell polarity and compensate for the loss of Wnt signaling. So et al. also identified three specific Wnt ligands – CWN-1, CWN-2 and EGL-20 – that collectively control the polarity of Z1 and Z4. Each protein has a distinct role: CWN-1 promotes Z1 and Z4 to have the same polarity, while CWN-2 induces the polarity of Z1 cells to reverse. EGL-20 then stops Z1 from regaining its original polarity and no longer mirroring the polarity of Z4. These findings shed new light on how Wnt signaling contributes to the mirror-symmetric structure of C. elegans gonads. It is possible that these proteins play similar roles in other animals to help regulate how organs form.
© 2024, So et al.