Wnt signaling drives WRM-1/ ␤-catenin asymmetries in early C. elegans embryos

Abstract

␤-Catenin regulates cell adhesion and cellular differentiation during development, and misregulation of ␤-catenin contributes to numerous forms of cancer in humans. Here we describe Caenorhabditis elegans conditional alleles of mom-2/Wnt, mom-4/Tak1, and wrm-1/␤-catenin. We use these reagents to examine the regulation of WRM-1/␤-catenin during a Wnt-signaling-induced asymmetric cell division. While WRM-1 protein initially accumulates in the nuclei of all cells, signaling promotes the retention of WRM-1 in nuclei of responding cells. We show that both PRY-1/Axin and the nuclear exportin homolog IMB-4/CRM-1 antagonize signaling. These findings reveal how Wnt signals direct the asymmetric localization of ␤-catenin during polarized cell division. Supplemental material is available at http://www.genesdev.org. Wnt proteins are secreted signaling molecules important in numerous developmental events in animals Caenorhabditis elegans provides an ideal system for analyzing the role of Wnt signaling in polarized cell divisions. In addition to powerful genetic tools available in this animal, signaling events can be analyzed at the level of the individual cells involved in signaling. For example, at the four-cell stage of embryogenesis, a ventral cell called EMS receives a signal from the posterior-most cell, P2. Signaling from P2 orients the EMS division axis onto the anterior-posterior (a/p) axis of the embryo (Bowerman and Shelton 1999) and induces an unequal division that gives rise to one anterior mesodermal precursor and one posterior endodermal precursor P2/EMS signaling involves multiple inputs, including at least two parallel cell-surface receptor-mediated pathways: the Wnt-Frizzled pathway Despite this progress, many gaps remain in our understanding of how P2/EMS signaling directs EMS spindle orientation and how this signaling leads to unequal POP-1 nuclear levels in the daughters of EMS. In particular, although the WRM-1/␤-catenin protein appears to represent a nexus for coordinating signals from the membrane and facilitating their transduction to the nucleus, little is known about whether and how WRM-1 activity or localization is regulated during signaling. Here we analyze the regulation of WRM-1 during the EMS cell division. We show that WRM-1ϻGFP initially enters the nucleus at the beginning of telophase in all cells but is exported in signal-nonresponding cells. Nuclear export requires the CRM-1-exportin homolog, IMB-4, and Ran-related molecules, including Ran-3/ RCC1 and Ran-5/RanBP3. Wnt signaling promotes the nuclear maintenance and/or continued accumulation of WRM-1 in daughter cells proximal to the polarizing signal. Our findings support a model for Wnt signaling-dependent polarized cell division in which signaling controls the nuclear accumulation of ␤-catenin