Igf1r Signaling Is Indispensable for Preimplantation Development and Is Activated via a Novel Function of E-cadherin

Insulin-like growth factor I receptor (Igf1r) signaling controls proliferation, differentiation, growth, and cell survival in many tissues; and its deregulated activity is involved in tumorigenesis. Although important during fetal growth and postnatal life, a function for the Igf pathway during preimplantation development has not been described. We show that abrogating Igf1r signaling with specific inhibitors blocks trophectoderm formation and compromises embryo survival during murine blastocyst formation. In normal embryos total Igf1r is present throughout the membrane, whereas the activated form is found exclusively at cell contact sites, colocalizing with E-cadherin. Using genetic domain switching, we show a requirement for E-cadherin to maintain proper activation of Igf1r. Embryos expressing exclusively a cadherin chimera with N-cadherin extracellular and E-cadherin intracellular domains (NcEc) fail to form a trophectoderm and cells die by apoptosis. In contrast, homozygous mutant embryos expressing a reverse-structured chimera (EcNc) show trophectoderm survival and blastocoel cavitation, indicating a crucial and non-substitutable role of the E-cadherin ectodomain for these processes. Strikingly, blastocyst formation can be rescued in homozygous NcEc embryos by restoring Igf1r signaling, which enhances cell survival. Hence, perturbation of E-cadherin extracellular integrity, independent of its cell-adhesion function, blocked Igf1r signaling and induced cell death in the trophectoderm. Our results reveal an important and yet undiscovered function of Igf1r during preimplantation development mediated by a unique physical interaction between Igf1r and E-cadherin indispensable for proper receptor activation and anti-apoptotic signaling. We provide novel insights into how ligand-dependent Igf1r activity is additionally gated to sense developmental potential in utero and into a bifunctional role of adhesion molecules in contact formation and signaling

N-cadherin can structurally substitute for E-cadherin during intestinal development but leads to polyp formation

We conditionally substituted E-cadherin (E-cad; cadherin 1) with N-cadherin (N-cad; cadherin 2) during intestine development by generating mice in which an Ncad cDNA was knocked into the Ecad locus. Mutant mice were born, demonstrating that N-cad can structurally replace E-cad and establish proper organ architecture. After birth, mutant mice gradually developed a mutant phenotype in both the small and large intestine and died at ~2-3 weeks of age, probably due to malnutrition during the transition to solid food. Molecular analysis revealed an extended domain of cells from the crypt into the villus region, with nuclear localization of β-catenin (β-cat; Ctnnb1) and enhanced expression of several β-cat target genes. In addition, the BMP signaling pathway was suppressed in the intestinal epithelium of the villi, suggesting that N-cad might interfere with BMP signaling in the intestinal epithelial cell layer. Interestingly, mutant mice developed severe dysplasia and clusters of cells with neoplastic features scattered along the crypt-villus axis in the small and large intestine. Our experimental model indicates that, in the absence of E-cad, the sole expression of N-cad in an epithelial environment is sufficient to induce neoplastic transformations

Beyond E-cadherin: roles of other cadherin superfamily members in cancer

Loss of cadherin 1 (CDH1; also known as epithelial cadherin (E-cadherin)) is used for the diagnosis and prognosis of epithelial cancers. However, it should not be ignored that the superfamily of transmembrane cadherin proteins encompasses more than 100 members in humans, including other classical cadherins, numerous protocadherins and cadherin-related proteins. Elucidation of their roles in suppression versus initiation or progression of various tumour types is a young but fascinating field of molecular cancer research. These cadherins are very diverse in both structure and function, and their mutual interactions seem to influence biological responses in complex and versatile ways

Heterotrimeric kinesin-II is necessary and sufficient to promote different stepwise assembly of morphologically distinct bipartite cilia in Drosophila antenna

Structurally distinct sensory cilia in the fly antenna grow in different stepwise patterns. The heterotrimeric kinesin-II is essential for growth at all stages, and it is also required for tubulin entry into the cilia from the beginning. This report establishes a primary function of the motor in the bipartite cilia assembly in Drosophila