Download Notchless Impacts Multiple Signaling Pathways During Pre

Notchless Impacts Multiple Signaling Pathways During Pre-Implantation
Development
Chiao-Ling Lo1,2, Jeremy B. Sherrill3 and Amy C. Lossie1,2,4
1
Department of Animal Science, 2PULSe Graduate Program, 3Department of Biological
Sciences, Purdue University, West Lafayette, IN; 4Department of Medicine, Indiana
University School of Medicine, Indianapolis, IN
Our interests lie in determining the genes and genetic pathways that are important for
establishing and maintaining maternal-fetal interactions during pregnancy. Through
positional cloning, we discovered that mutations in Notchless (Nle1) lead to embryonic
lethality during peri-implantation in mice. NLE1 is a member of the WD40-repeat protein
family, and is thought to signal via the canonical Notch pathway. In invertebrates and
lower vertebrates, the Notch pathway directs cell fate prior to gastrulation. However,
gene targeting studies demonstrate that Notch signaling is dispensable for gastrulation
in mice. The phenotype of Nle1 mutant embryos is much more severe than single Notch
receptor mutations or even in animals where Notch signaling is blocked. To test the
hypothesis that Nle1 functions in multiple signaling pathways during pre-implantation
development, we examined expression of Notch downstream target genes, as well as
select members of the Wnt pathway in wild-type and mutant embryos. We saw no
indication that the Notch pathway is disrupted in mutant embryos; Notch receptors,
ligands and downstream targets showed normal expression levels. Instead, we found
that members of the Wnt pathway are downregulated in Nle1 mutants, while Cdkn1a
was upregulated. Our data implicate NLE1 in WNT signaling and cell cycle arrest via
CDKN1A-mediated apoptosis. Intriguingly, WNT signaling is critical for gastrulation in
mice. Deletion of Wnt3 leads to failure prior to primitive streak formation, and multiple
ligands and receptors are detected in blastocysts and the uterus during peri-implantation.
These pathways could provide novel targets for the design of therapeutic interventions
for infertility.