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ENU mutagenesis reveals that Notchless homolog 1 (Drosophila) affects Cdkn1a and several members of the Wnt pathway during murine pre-implantation development.

BMC genetics | Dec 12, 2012

BACKGROUND: Our interests lie in determining the genes and genetic pathways that are important for establishing and maintaining maternal-fetal interactions during pregnancy. Mutation analysis targeted to a 34 Mb domain flanked by Trp53 and Wnt3 demonstrates that this region of mouse chromosome 11 contains a large number of essential genes. Two mutant alleles (l11Jus1 and l11Jus4), which fall into the same complementation group, survive through implantation but fail prior to gastrulation. RESULTS: Through a positional cloning strategy, we discovered that these homozygous mutant alleles contain non-conservative missense mutations in the Notchless homolog 1 (Drosophila) (Nle1) gene. NLE1 is a member of the large WD40-repeat protein family, and is thought to signal via the canonical NOTCH pathway in vertebrates. However, the phenotype of the Nle1 mutant mice is much more severe than single Notch receptor mutations or even in animals in which NOTCH signaling is blocked. To test the hypothesis that NLE1 functions in multiple signaling pathways during pre-implantation development, we examined expression of multiple Notch downstream target genes, as well as select members of the Wnt pathway in wild-type and mutant embryos. We did not detect altered expression of any primary members of the Notch pathway or in Notch downstream target genes. However, our data reveal that Cdkn1a, a NOTCH target, was upregulated in Nle1 mutants, while several members of the Wnt pathway are downregulated. In addition, we found that Nle1 mutant embryos undergo caspase-mediated apoptosis as hatched blastocysts, but not as morulae or blastocysts. CONCLUSIONS: Taken together, these results uncover potential novel functions for NLE1 in the WNT and CDKN1A pathways during embryonic development in mammals.

Pubmed ID: 23231322 RIS Download

Mesh terms: Animals | Cyclin-Dependent Kinase Inhibitor p21 | Embryonic Development | Ethylnitrosourea | Female | Gene Expression Regulation, Developmental | Mice | Microfilament Proteins | Mutagenesis | Mutation | Pregnancy | Pregnancy, Animal | Wnt Signaling Pathway

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Associated grants

  • Agency: NCI NIH HHS, Id: R01 CA115503
  • Agency: NICHD NIH HHS, Id: U01 HD039372
  • Agency: NICHD NIH HHS, Id: 5F32HD44407
  • Agency: NICHD NIH HHS, Id: U01HD39372

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Mutant Mouse Regional Resource Centers

Repository of spontaneous and induced mutant mouse and cell lines. It includes breeding/distribution facilities and an information coordinating center. Mice strains are cryopreserved, unless a live colony must be established. Live mice are supplied from a production colony, from a colony recovered from cryopreservation, or via micro-injection of a cell line into host blastocysts. MMRRC member facilities also develop technologies to improve the handling of mutant mice, including advances in assisted reproductive techniques, cryobiology, genetic analysis, phenotyping and infectious disease diagnostics.

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