Notchless Interacts with Multiple Signaling Pathways during Mouse Peri-Implantation Development

<p>During peri-implantation, the embryo transitions from a suspension environment in the fallopian tubes to an adherent system within the uterus. Successful transition requires maternal and fetal signaling cascades that establish maternal-fetal boundaries. Failure is common, as ~ 25% of all human pregnancies terminate during these steps. A large-scale mutation study in mice produced two mutants (l11Jus1 and l11Jus4) that are excellent models of this transition. l11Jus1 and l11Jus4 contain missense mutations in the Notchless homolog 1 (Drosophila) (Nle1) gene. NLE1 is thought to signal via the canonical NOTCH pathway in vertebrates. Although in invertebrates and lower vertebrates, NOTCH signaling directs cell fate prior to gastrulation, it is dispensable for gastrulation in mice. Moreover, in yeast and plants, which lack NOTCH signaling, Nle1 is crucial for ribosome biogenesis. These seemingly contradictory data led me to hypothesize that mutation of Nle1 causes a lethal trauma to the embryo that disrupts multiple signaling pathways during peri-implantation development. I present data that: 1. Refute the presumption that Nle1 functions as a negative regulator of NOTCH during pre-implantation development; 2. Demonstrate that mutations in Nle1 lead to mis-expression of several members of the Wnt pathway; and 3. Show that mutant embryos enter cell cycle arrest; when that fails, they undergo p53-mediated programmed cell death. To understand the trauma(s) that precipitated these lethal cascades, I discovered that Nle1 mutants display delays in ribosomal RNA processing and nucleogenesis. These results uncover novel functions for NLE1 in the ribosomal biogenesis, TRP53 and WNT pathways during mammalian embryonic development.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Animal Science

Year

2013

Author dc:creator

• Lo, Chiao-Ling

Contributors dc:contributor

• Amy C. Lossie
• Ann L. Kirchmaier
• Shihuan Kuang
• Yuk Fai Leung

• notchless
• notch pathway
• p53
• preimplantation development
• ribosomal biogenesis
• wnt pathway
• Animal Sciences
• Genetics

Repository record dc:identifier

https://docs.lib.purdue.edu/open_access_dissertations/105

OAI identifier oai:identifier

oai:docs.lib.purdue.edu:open_access_dissertations-1110