Dataset Information

Wnt signaling and CEH-22/tinman/Nkx2.5 specify a stem cell niche in C. elegans.

ABSTRACT: Wnt signaling regulates many aspects of metazoan development, including stem cells. In C. elegans, Wnt/MAPK signaling controls asymmetric divisions. A recent model proposed that the POP-1/TCF DNA binding protein works together with SYS-1/beta-catenin to activate transcription of target genes in response to Wnt/MAPK signaling. The somatic gonadal precursor (SGP) divides asymmetrically to generate distal and proximal daughters of distinct fates: only its distal daughter generates a distal tip cell (DTC), which is required for stem cell maintenance. No DTCs are produced in the absence of POP-1/TCF or SYS-1/beta-catenin, and extra DTCs are made upon overexpression of SYS-1/beta-catenin. Here we report that POP-1/TCF and SYS-1/beta-catenin directly activate transcription of ceh-22/nkx2.5 isoforms in SGP distal daughters, a finding that confirms the proposed model of Wnt/MAPK signaling. In addition, we demonstrate that the CEH-22/Nkx2.5 homeodomain transcription factor is a key regulator of DTC specification. We speculate that these conserved molecular regulators of the DTC niche in nematodes may provide insight into specification of stem cell niches more broadly.

SUBMITTER: Lam N

PROVIDER: S-EPMC1637041 | biostudies-literature | 2006 Feb

REPOSITORIES: biostudies-literature

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Wnt signaling and CEH-22/tinman/Nkx2.5 specify a stem cell niche in C. elegans.

Lam Ngan N Chesney Michael A MA Kimble Judith J

Current biology : CB 20060201 3

Wnt signaling regulates many aspects of metazoan development, including stem cells. In C. elegans, Wnt/MAPK signaling controls asymmetric divisions. A recent model proposed that the POP-1/TCF DNA binding protein works together with SYS-1/beta-catenin to activate transcription of target genes in response to Wnt/MAPK signaling. The somatic gonadal precursor (SGP) divides asymmetrically to generate distal and proximal daughters of distinct fates: only its distal daughter generates a distal tip cell ...[more]

PMID: 16461282

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Project description:?-Catenin-dependent Wnt signaling is initiated as Wnt binds to both the receptor FZD and coreceptor LRP5/6, which then assembles a multimeric complex at the cytoplasmic membrane face to recruit and inactivate the kinase GSK3. The large number and sequence diversity of Wnt isoforms suggest the possibility of domain-specific ligand-coreceptor interactions, and distinct binding sites on LRP6 for Wnt3a and Wnt9b have recently been identified in vitro. Whether mechanistically different interactions between Wnts and coreceptors might mediate signaling remains to be determined. It is also not clear whether coreceptor homodimerization induced extracellularly can activate Wnt signaling, as is the case for receptor tyrosine kinases. We generated monoclonal antibodies against LRP6 with the unexpected ability to inhibit signaling by some Wnt isoforms and potentiate signaling by other isoforms. In cell culture, two antibodies characterized further show reciprocal activities on most Wnts, with one antibody antagonizing and the other potentiating. We demonstrate that these antibodies bind to different regions of LRP6 protein, and inhibition of signaling results from blocking Wnt binding. Antibody-mediated dimerization of LRP6 can potentiate signaling only when a Wnt isoform is also able to bind the complex, presumably recruiting FZD. Endogenous autocrine Wnt signaling in different tumor cell lines can be either antagonized or enhanced by the LRP6 antibodies, indicating expression of different Wnt isoforms. As anticipated from the roles of Wnt signaling in cancer and bone development, antibody activities can also be observed in mice for inhibition of tumor growth and in organ culture for enhancement of bone mineral density. Collectively, our results indicate that separate binding sites for different subsets of Wnt isoforms determine the inhibition or potentiation of signaling conferred by LRP6 antibodies. This complexity of coreceptor-ligand interactions may allow for differential regulation of signaling by Wnt isoforms during development, and can be exploited with antibodies to differentially manipulate Wnt signaling in specific tissues or disease states.

Dataset Information

Wnt signaling and CEH-22/tinman/Nkx2.5 specify a stem cell niche in C. elegans.

Publications

Wnt signaling and CEH-22/tinman/Nkx2.5 specify a stem cell niche in C. elegans.

Similar Datasets

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