Syndactyly in a novel Fras1^rdf mutant results from interruption of signals for interdigital apoptosis

Abstract

Fras1 encodes an extracellular matrix protein that is critical for the establishment of the epidermal basement membrane during gestation. In humans, mutations in FRAS1 cause Fraser Syndrome (FS), a pleiotropic condition with many clinical presentations such as limb, eye, kidney, and craniofacial deformations. Many of these defects are mimicked by loss of Fras1 in mice, and are preceded by the formation of epidermal blisters in utero. In this study, we identified a novel ENU-derived rounded foot (rdf) mouse mutant with highly penetrant hindlimb soft-tissue syndactyly among other structural defects. Mapping and sequencing revealed that rdf is a novel loss-of-function nonsense allele of Fras1 (Fras1rdf). Focusing on the limb, we found that the Fras1rdf syndactyly phenotype originates from loss of interdigital cell death (ICD). Despite normal expression of BMP ligands and their receptors, the BMP downstream target gene Msx2, which is also necessary and sufficient to promote ICD, was downregulated in the interdigital regions of Fras1rdf hindlimb buds. The close correlation between limb bud epidermal blistering, decreased Msx2 expression and reduced ICD suggest that epithelium detachment from the mesenchyme may create a physical gap that interrupts the transmission of BMP among other signals, resulting in soft tissue syndactyly.

Fraser extracellular matrix complex subunit 1 promotes liver metastasis of gastric cancer

“…FRAS1 is similar in function to collagen VII and plays a significant role in epithelial–stromal adhesion during mouse embryogenesis . Patients with Fraser syndrome, a genetic disorder, present with congenital malformations such as cryptophthalmos, syndactylism and reno‐urinary anomalies caused by FRAS1 mutations …”

“…19 Patients with Fraser syndrome, a genetic disorder, present with congenital malformations such as cryptophthalmos, syndactylism and reno-urinary anomalies caused by FRAS1 mutations. 20,21 FRAS1 is associated with cancers. For example, a FRAS1-knockdown in a lung cancer cell line inactivates the FAK pathway and suppresses tumor invasion and migration.…”

Fraser syndrome: review of the literature illustrated by a historical adult case

“…The incidence of consanguinity in families with FS is estimated reaching 15% to 30% 2,4,7,27 . This syndrome seems to be related to a failure of the apoptosis program and to the formation of large blisters during embryonic development due to defects in epidermal adhesion (disruption of the epithelial-mesenchymal interactions) [28][29][30] . Indeed, in embryos, the Fraser complex (FC) mediates epithelial-connective tissue interactions.…”

A Review of the Genetics and Pathogenesis of Syndactyly in Humans and Experimental Animals: A 3-Step Pathway of Pathogenesis

“…Mutations in FRAS1 in humans cause Fraser syndrome (OMIM 219000) with eye, kidney, and craniofacial defects [48]. Hines et al [49] identified a novel ENU-derived rounded foot (rdf) mouse mutant with hindlimb cutaneous syndactyly caused by loss-of-function nonsense allele of Fras1 . The primary defect in these animals was the decreased Msx2 expression [49].…”

“…Hines et al [49] identified a novel ENU-derived rounded foot (rdf) mouse mutant with hindlimb cutaneous syndactyly caused by loss-of-function nonsense allele of Fras1 . The primary defect in these animals was the decreased Msx2 expression [49]. As mentioned above, deficiency of Msx1/2 is associated with extended Fgf activity in the AER [47].…”