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Nle1 mutants more severe than single Notch mutants or disruption of Notch signaling

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Nle1 mutants more severe than single Notch mutants or disruption of Notch signaling

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  1. Taking a different pathway: Nle1 plays with Wntduring embryogenesisAmy C. Lossie1,2, Chiao-Ling Lo1,3and Jeremy B. Sherrill1,41Department of Animal Science, Purdue University, West Lafayette, IN; 2Dept of Medicine, Indiana University School of Medicine, Indianapolis, IN; 3PULSe Interdisciplinary Graduate Program, Purdue University, West Lafayette, IN; 4Department of Biological Sciences, Purdue University, West Lafayette, IN.
 Our interests lie in understanding the genetic pathways and epigenetic factors that are important for establishing and maintaining maternal-fetal interactions during pregnancy. Notch mutants are less severe than Nle1 mutants Miscarriage • 50% of mammalian pregnancies result in fetal loss by peri-implantation (Rai and Regan, 2006) • 15% chance in women under 35 • 25% chance in women under 40 • Recurrent miscarriage (3 consecutive) occurs in ~1% of the population • Nle1 mutants more severe than single Notch mutants ordisruption of Notch signaling • Mice undergo gastrulation in the absence of Notch signaling • ICM from Nle1 KO mice fails to grow • Mutants undergo apoptosis at E3.5 plus 1 day in culture (Cormier et al., 2006) L1 & L4 are excellent models of miscarriage Is Trp53 upregulated in mutants? Nle1 encodes a WD40 Repeat Protein • Trp53 is not upregulated in mutants at the morula, blastocyst or hatched blastocyst stage Conclusions Katherine Baumgarner Notch PCR Array at E3.5 • NLE1 is not a positive regulator of Notch signaling during pre-implantaiton development • NLE1 acts via multiple pathways during embryonic development The Notch Pathway • Downstream targets will be downregulated • Notch receptors & ligands will be upregulated Notch Wnt • No misregulation of downstream target genes or members of the Notch pathway • Cdkn1a is upregulated (p=1.9 X 10-8) • Fzd4, Fzd7 and Wnt11 are downregulated Future Studies • Examine acetylated form of p53 • Examine expression of miR-34a • Examine other genes involved in cell-cycle arrest or apoptosis (Bcl2) • Investigate whether Nle1 acts in the Notch pathway at later stages • NLE1 binds NICD in Drosophila andXenopus(Royet et al., 1998; Cormier et al., 2006) • Disruption of the Notch pathway in lower vertebrates does not affect mesoderm induction Summary • L1 and L4 have mutations in Nle1 • L1 and L4phenocopythe Nle1-/- knockout • Cdkn1a is upregulated in mutants at all stages • Wnt pathway genes are downregulated Notch Figure modifiedfromHaltiwanger R.S. and Lowe J.B. 2004. Annu. Rev. Biochem

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