Dataset Information

A conserved Six-Eya cassette acts downstream of Wnt signaling to direct non-myogenic versus myogenic fates in the C. elegans postembryonic mesoderm.

ABSTRACT: The subdivision of mesodermal cells into muscle and non-muscle cells is crucial to animal development. In the C. elegans postembryonic mesoderm, this subdivision is a result of an asymmetric cell division that leads to the formation of striated body wall muscles and non-muscle coelomocytes. Here we report that the Six homeodomain protein CEH-34 and its cofactor Eyes Absent, EYA-1, function synergistically to promote the non-muscle fate in cells also competent to form muscles. We further show that the asymmetric expression of ceh-34 and eya-1 is regulated by a combination of 1) mesodermal intrinsic factors MAB-5, HLH-1 and FOZI-1, 2) differential POP-1 (TCF/LEF) transcriptional activity along the anterior-posterior axis, and 3) coelomocyte competence factor(s). These factors are conserved in both vertebrates and invertebrates, suggesting a conserved paradigm for mesoderm development in metazoans.

SUBMITTER: Amin NM

PROVIDER: S-EPMC2703692 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

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A conserved Six-Eya cassette acts downstream of Wnt signaling to direct non-myogenic versus myogenic fates in the C. elegans postembryonic mesoderm.

Amin Nirav M NM Lim Sung-Eun SE Shi Herong H Chan Tiffany L TL Liu Jun J

Developmental biology 20090508 2

The subdivision of mesodermal cells into muscle and non-muscle cells is crucial to animal development. In the C. elegans postembryonic mesoderm, this subdivision is a result of an asymmetric cell division that leads to the formation of striated body wall muscles and non-muscle coelomocytes. Here we report that the Six homeodomain protein CEH-34 and its cofactor Eyes Absent, EYA-1, function synergistically to promote the non-muscle fate in cells also competent to form muscles. We further show tha ...[more]

PMID: 19427847

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Project description:BACKGROUND:Aberrant Wnt/?-catenin signaling is associated with breast cancer even though genetic mutations in Wnt signaling components are rare. We have previously demonstrated that Rad6B, an ubiquitin conjugating enzyme, stabilizes ?-catenin via polyubiqutin modifications that render ?-catenin insensitive to proteasomal degradation. Rad6B is a transcriptional target of ?-catenin, creating a positive feedback loop between Rad6B expression and ?-catenin activation. METHODS:To isolate subpopulations expressing high or low Rad6B levels, we transfected MDA-MB-231 or WS-15 human breast cancer cells with ZsGreen fluorescent reporter vector in which the expression of ZsGreen was placed under the control of Rad6B promoter. ZsGreenhigh and ZsGreenlow subpopulations, reflective of high and low Rad6B promoter activity, respectively, were isolated by FACS. To determine the relevance of Wnt signaling in Rad6B-mediated ?-catenin stabilization/activation, the ZsGreenhigh cells were transfected with signaling-defective Wnt coreceptor LRP6?173. Rad6B expression and promoter activity were determined by RT-PCR, Western blot and Rad6B promoter-mediated luciferase assays. ?-catenin levels and transcriptional activity were determined by Western blot and TOP/FOP Flash reporter assays. Tumor formation and morphologies of ZsGreenlow, ZsGreenhigh, and ZsGreenhigh/LRP6?173 cells compared to unsorted vector controls were evaluated in nude mice. Expression of Wnt signaling related genes was profiled using the Wnt signaling pathway RT2 Profiler PCR arrays. RESULTS:ZsGreenhigh subpopulations showed high Rad6B expression and Rad6B promoter activity as compared to ZsGreenlow cells. ZsGreenhigh (high Rad6B expressors) also showed elevated ?-catenin levels and TOP/Flash activity. Inhibiting Wnt signaling in the high Rad6B expressors decreased ZsGreen fluorescence, Rad6B gene expression, ?-catenin levels and TOP/Flash activity. Tumors derived from high Rad6B expressors were predominantly composed of cells with epithelial mesenchymal transition (EMT) phenotype as compared to control tumors that were composed of both cuboidal and EMT-type cells. Tumors derived from low Rad6B expressors lacked EMT phenotype. Inhibition of LRP6 function in the high Rad6B expressors abrogated the EMT phenotype. Gene expression profiling showed upregulation of several Wnt signaling pathway regulators in high Rad6B expressors that were downregulated by interference of Wnt signaling with mutant LRP6 or by Rad6B silencing. CONCLUSIONS:These data reveal a functional link between the canonical Wnt pathway and Rad6B in ?-catenin activation and breast cancer progression.

Project description:BackgroundThe Pax-Six-Eya-Dach network (PSEDN) is involved in a variety of developmental processes, including well documented roles in determination of sensory organs and morphogenesis in bilaterian animals. Expression of PSEDN components in cnidarians is consistent with function in sensory organ development. Recent work in demosponges demonstrated the presence of single homologs of Pax and Six genes, and their possible involvement in morphogenesis, but the absence of the remaining network components. Calcisponges are evolutionarily distant from demosponges, and the developmental toolkits of these two lineages differ significantly. We used an emerging model system, Sycon ciliatum, to identify components of the PSEDN and study their expression during embryonic and postembryonic development.ResultsWe identified two Pax, three Six and one Eya genes in calcisponges, a situation strikingly different than in the previously studied demosponges. One of the calcisponge Pax genes can be identified as PaxB, while the second Pax gene has no clear affiliation. The three calcisponge Six genes could not be confidently classified within any known family of Six genes. Expression analysis in adult S. ciliatum demonstrated that representatives of Pax, Six and Eya are expressed in patterns consistent with roles in morphogenesis of the choanocyte chambers. Distinct paralogues of Pax and Six genes were expressed early in the development of the putative larval sensory cells, the cruciform cells. While lack of known photo pigments in calcisponge genomes precludes formal assignment of function to the cruciform cells, we also show that they express additional eumetazoan genes involved in specification of sensory and neuronal cells: Elav and Msi.ConclusionsOur results indicate that the role of a Pax-Six-Eya network in morphogenesis likely predates the animal divergence. In addition, Pax and Six, as well as Elav and Msi are expressed during differentiation of cruciform cells, which are good candidates for being sensory cells of the calcaronean sponge larvae.

Dataset Information

A conserved Six-Eya cassette acts downstream of Wnt signaling to direct non-myogenic versus myogenic fates in the C. elegans postembryonic mesoderm.

Publications

A conserved Six-Eya cassette acts downstream of Wnt signaling to direct non-myogenic versus myogenic fates in the C. elegans postembryonic mesoderm.

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