A Cdh1^HA knock‐in allele rescues the Cdh1^−/− phenotype but shows essential Cdh1 function during placentation

Abstract

The specific roles of classical cadherins at key morphogenetic events during development are still not fully understood. As part of a project to study cadherin function during early mammalian development, we generated mice carrying an HA-epitope tagged Cdh1 (E-cadherin) cDNA knocked into the Cdh1 locus, similar to the previously described mouse mutants in which we forced Cdh2 (N-cadherin) expression in the Cdh1 expression domain. As expected and in contrast to Cdh1Cdh2/Cdh2 and Cdh1 2/2, our Cdh1HA/HA mutant embryos form proper trophectoderm, implant and undergo both gastrulation and neurulation. However, Cdh1 HA/HA mice display an unexpected phenotype at embryonic day 10.5. Cdh1 HA/HA embryos are smaller, paler and suffer from an insufficient nutrient supply. We detected a reduced expression of Cdh1 HA specifically in the extraembryonic ectoderm and in the labyrinth layer, whereas expression in the embryo proper was normal. With this approach, we show for the first time that Cdh1 is essential for the correct formation of the placenta. Placentas without Cdh1 expression are impaired and incapable of establishing a proper connection between the embryonic and the maternal blood vessels for efficient nutrient and oxygen transport. Developmental Dynamics 239:2330-2344,

A Grhl2-dependent gene network controls trophoblast branching morphogenesis

“…Importantly, previous studies have revealed that structural defects of basement membranes at the chorioallantoic interface of collagen IV (Col4a1/ Col4a2)-mutant mice resulted in impaired placental labyrinth formation (Pöschl et al, 2004). Moreover, disruption of Cdh1 expression is associated with defective labyrinth development (Stemmler and Bedzhov, 2010). Thus, the defects of BCT cells in Grhl2 mutants reasonably explain the observed failure of labyrinth formation.…”

Nucleotide variants of the cancer predisposing gene CDH1 and the risk of non-syndromic cleft lip with or without cleft palate

“…Further in vitro and in vivo functional studies are needed to characterize the functional significance of this SNP. Loss of expression of E-cadherin leads to an increased ability of cells to invade neighboring tissues [10, 16]. Our findings are of interest especially in light of observations showing that individuals without a CDH1 mutation that are presenting with tumors that have E-cadherin expression impairment, similar to that observed in CDH1 germline mutation carriers with HDGC, may have a CDH1 expression defect caused be either direct or indirect mechanisms targeting the CDH1 genomic sequence [24].…”

“…Abnormal CDH1 expression has been linked to many human diseases, including tumors, nephrolithiasis, pre-eclampsia, and ectopic pregnancy [10, 11]. Although great advances have been achieved in gene identification for NSCL/P, the underlying molecular mechanisms remain obscure.…”

“…Leitra et al [27] and Rafighdoost et al [20] have suggested that CDH1 may be a very reasonable candidate gene for NSCL/P. In mammals, CDH1 is required during early development and in establishing a proper connection between embryonic and maternal blood vessels [10]. It is expressed in the epithelium of the palate prior to and after shelf fusion.…”

“…Approximately 25–48 % of the individuals with HDGC have an autosomal dominant inherited germline CDH1 mutation or large deletion affecting the CDH1 locus. The CDH1 gene, located on chromosome 16q22.1, encodes E-cadherin (OMIM: *192090), which is involved in epithelial calcium-dependent cell-to-cell adhesion [10, 11]. Currently, there are no reliable clinical screening methods for early detection of HDGC, which is located submucosally.…”