Abstract
Wnt signaling controls various aspects of developmental and cell biology, as well as contributing to certain cancers. Expression of the human Rho family small GTPase Wrch/RhoU is regulated by Wnt signaling, and Wrch and its paralog Chp/RhoV are both implicated in oncogenic transformation and regulation of cytoskeletal dynamics. We performed developmental genetic analysis of the single Caenorhabditis elegans ortholog of Chp and Wrch, CHW-1. Using a transgenic assay of the distal tip cell migration, we found that wild-type CHW-1 is likely to be partially constitutively active and that we can alter ectopic CHW-1-dependent migration phenotypes with mutations predicted to increase or decrease intrinsic GTP hydrolysis rate. The vulval P7.p polarity decision balances multiple antagonistic Wnt signals, and also uses different types of Wnt signaling. Previously described cooperative Wnt receptors LIN-17/Frizzled and LIN-18/Ryk orient P7.p posteriorly, with LIN-17/Fz contributing approximately two-thirds of polarizing activity. CHW-1 deletion appears to equalize the contributions of these two receptors. We hypothesize that CHW-1 increases LIN-17/Fz activity at the expense of LIN-18/Ryk, thus making the contribution of these signals unequal. For P7.p to polarize correctly and form a proper vulva, LIN-17/Fz and LIN-18/Ryk antagonize other Wnt transmembrane systems VANG-1/VanGogh and CAM-1/Ror. Our genetic data suggest that LIN-17/Fz represses both VANG-1/VanGogh and CAM-1/Ror, while LIN-18/Ryk represses only VANG-1. These data expand our knowledge of a sophisticated signaling network to control P7.p polarity, and suggests that CHW-1 can alter ligand gradients or receptor priorities in the system.
Highlights
Rho family small GTPases are intracellular signaling molecules that regulate cytoskeletal rearrangements and transcription, and which affect diverse cellular processes including cell adhesion, polarity, and migration [1]
Using genetic epistasis analysis we show that CHW-1 affects LIN-17/Fz and LIN-18/Ryk differently; loss of chw-1 suppresses the lin-17 P-Rvl phenotype, but enhances the lin-18 P-Rvl phenotype, a pattern not yet described for any other proteins functioning in this system
We found that loss of CHW-1 had different effects in cam-1 or vang-1 mutant backgrounds (Table 5). chw-1-directed RNA interference (RNAi) did not alter suppression of lin-17; by cam-1 in the triple mutant compared to the gfp-directed RNAi control (Table 5, line 5 vs. 4)
Summary
Rho family small GTPases are intracellular signaling molecules that regulate cytoskeletal rearrangements and transcription, and which affect diverse cellular processes including cell adhesion, polarity, and migration [1]. The large majority of studies concerning Rho family GTPases have focused on the canonical members RhoA, Rac, and Cdc. Two of the less studied Rho family GTPases are the closely related Cdc subfamily proteins Wnt-regulated Cdc homolog-1 (Wrch-1/RhoU) and Cdc homologous protein (Chp/Wrch-2/RhoV). Wrch-1 was first identified as a gene whose expression increased when the Wnt signaling pathway was activated [3]. Wnt-dependent expression of Wrch-1 does not require β- catenin, but does require c-Jun N-terminal kinase (JNK), implicating the non-canonical Wnt/Planar Cell Polarity (PCP) pathway [3, 5]
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