Wnt signaling plays important roles in cell polarization in diverse organisms, and loss of cell polarity is an early event in tumorigenesis caused by mutations in Wnt pathway genes. Despite this, the precise roles of Wnt proteins in cell polarization have remained elusive. In no organism has it been shown that the asymmetric position of a Wnt signal is essential to establishing a cell's polarity. Attempts to test this by ubiquitous expression of Wnt genes have suggested that Wnt signals might act only as permissive factors in cell polarization. Here we find, by using cell manipulations and ectopic gene expression in C. elegans, that the position from which Wnt signals are presented can determine the polarity of both embryonic and postembryonic cells. Furthermore, the position from which a Wnt signal is presented can determine the polarity of Frizzled receptor localization, suggesting that the polarizing effect of Wnt is likely to be direct. These results demonstrate that Wnt proteins can function as positional cues in establishing cell polarity.

␤-Catenin can promote adhesion at the cell cortex and mediate Wnt signaling in the nucleus. We show that, in Caenorhabditis elegans, both WRM-1/␤-catenin and LIT-1 kinase localize to the anterior cell cortex during asymmetric cell division but to the nucleus of the posterior daughter afterward. Both the cortical and nuclear localizations are regulated by Wnts and are apparently coupled. We also found that the daughters show different nuclear export rates for LIT-1. Our results indicate that Wnt signals release cortical WRM-1 from the posterior cortex to generate cortical asymmetry that may control WRM-1 asymmetric nuclear localization by regulating cell polarity.Supplemental material is available at htttp://www.genesdev.org. Asymmetric cell division is a fundamental mechanism for producing cellular diversity (Horvitz and Herskowitz 1992). Asymmetric division often involves the polarized localization and segregation of cell-fate determinants. In Drosophila, the Numb and Prospero proteins are cellfate determinants that are asymmetrically segregated into one of the daughter cells (ganglion mother cell [GMC]) (Betschinger and Knoblich 2004;Roegiers and Jan 2004). During neuroblast divisions, these proteins localize to the basal side of the cell cortex where they are segregated into the GMC. The asymmetric localizations of these molecules are regulated by Bazooka/Par-3, Par-6, and aPKC, which localize to the opposite side, i.e., the apical cell cortex. Similarly, in the Caenorhabditis elegans embryo at the one-cell stage, PAR-3, PAR-6, and aPKC localize to the anterior cortex (Kemphues 2000). Although the mechanisms are not clearly understood, these molecules control the localization of fate determinants (Numb and Prospero in Drosophila and P granules in C. elegans) to the opposite side of the cells through the regulation of cell polarity. Therefore, the cortical localization of polarity regulators appears to play important roles in asymmetric cell division, although this has not been clearly demonstrated.After the four-cell stage of C. elegans development, the polarity of many cells, including the EMS blastomere and the T hypodermal cell, is regulated by the Wnt signaling pathway (Thorpe et al. 2000;Korswagen 2002). Unlike the tissue-polarity Wnt pathway, which regulates cell polarity in Drosophila and mammals independent of ␤-catenin (Adler 2002), the Wnt pathway that controls the EMS polarity involves WRM-1/␤-catenin and the POP-1/TCF transcription factor and hence is related to the canonical Wnt pathway. Unlike ␤-catenin in other organisms, WRM-1 does not bind to cadherins and functions in Wnt signaling only, but not in cell adhesion (Korswagen et al. 2000). In the canonical Wnt pathway, the Wnt signal regulates the stability and nuclear localization of ␤-catenin (Logan and Nusse 2004). However, it is not known how the Wnt signal regulates WRM-1, especially because WRM-1 does not have the conserved phosphorylation sites of GSK3␤. Furthermore, the subcellular localization of WRM-1 has not been determined. Therefor...

The maintenance of cell fate is important for normal development and tissue homeostasis. Epigenetic mechanisms, including histone modifications, are likely to play crucial roles in cell-fate maintenance. However, in contrast to the established functions of histone methylation, which are mediated by the polycomb proteins, the roles of histone acetylation in cell-fate maintenance are poorly understood. Here, we show that the C. elegans acetylated-histone-binding protein BET-1 is required for the establishment and maintenance of stable fate in various lineages. In most bet-1 mutants, cells adopted the correct fate initially, but at later stages they often transformed into a different cell type. By expressing BET-1 at various times in development and examining the rescue of the Bet-1 phenotype, we showed that BET-1 functions both at the time of fate acquisition, to establish a stable fate, and at later stages, to maintain the established fate. Furthermore, the disruption of the MYST HATs perturbed the subnuclear localization of BET-1 and caused bet-1-like phenotypes, suggesting that BET-1 is recruited to its targets through acetylated histones. Our results therefore indicate that histone acetylation plays a crucial role in cell-fate maintenance.

During development, cell polarization is often coordinated to harmonize tissue patterning and morphogenesis. However, how extrinsic signals synchronize cell polarization is not understood. In Caenorhabditis elegans, most mitotic cells are polarized along the anterior-posterior axis and divide asymmetrically. Although this process is regulated by a Wnt-signaling pathway, Wnts functioning in cell polarity have been demonstrated in only a few cells. We analyzed how Wnts control cell polarity, using compound Wnt mutants, including animals with mutations in all five Wnt genes. We found that somatic gonadal precursor cells (SGPs) are properly polarized and oriented in quintuple Wnt mutants, suggesting Wnts are dispensable for the SGPs' polarity, which instead requires signals from the germ cells. Thus, signals from the germ cells organize the C. elegans somatic gonad. In contrast, in compound but not single Wnt mutants, most of the six seam cells, V1–V6 (which are epithelial stem cells), retain their polarization, but their polar orientation becomes random, indicating that it is redundantly regulated by multiple Wnt genes. In contrast, in animals in which the functions of three Wnt receptors (LIN-17, MOM-5, and CAM-1) are disrupted—the stem cells are not polarized and divide symmetrically—suggesting that the Wnt receptors are essential for generating polarity and that they function even in the absence of Wnts. All the seam cells except V5 were polarized properly by a single Wnt gene expressed at the cell's anterior or posterior. The ectopic expression of posteriorly expressed Wnts in an anterior region and vice versa rescued polarity defects in compound Wnt mutants, raising two possibilities: one, Wnts permissively control the orientation of polarity; or two, Wnt functions are instructive, but which orientation they specify is determined by the cells that express them. Our results provide a paradigm for understanding how cell polarity is coordinated by extrinsic signals.

The SWI/SNF-like chromatin remodeling complexes consist of two evolutionarily conserved subclasses, which are characterized by specific accessory components, the OSA/BAF250 and Polybromo proteins. These complexes regulate the expressions of distinct sets of target genes, with some overlap, and the regulatory components are thought to determine the target specificity for each complex. Here we isolated C. elegans mutants of the genes for the OSA/BAF250 homolog, LET-526, and the Polybromo homolog, PBRM-1, in a screen for the abnormal asymmetric cell division phenotype. In the asymmetric division of the T cell, both LET-526 and PBRM-1 regulated the asymmetric expression of psa-3/Meis between the T cell daughters, suggesting that the two subclasses share the same target. In the gonad, PBRM-1 regulated gonad primordium formation during embryogenesis, whereas LET-526 was required post-embryonically for distal tip cell (DTC) production from the gonad primordium, suggesting that these proteins have distinct targets for DTC development. Thus, the same cellular process is regulated by LET-526 and PBRM-1 in the asymmetric division of the T cell, but they regulate distinct cellular processes in the gonad morphogenesis. Although disruption of the core component PSA-1 or PSA-4 caused similar defects in the gonad and T cell, it also caused early embryonic arrest, which was not observed in the let-526, pbrm-1, or let-526 pbrm-1 double mutants, suggesting that some targets of SWI/SNF-like complexes do not require LET-526 or PBRM-1 for their transcription. Our results show that the target selection by SWI/SNF-like complexes during C. elegans development is intricately regulated by accessory components.