BACKGROUND: 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. RESULTS: 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 (Fras1(rdf)). Focusing on the limb, we found that the Fras1(rdf) syndactyly phenotype originates from loss of interdigital cell death (ICD). Despite normal expression of bone morphogenetic protein (BMP) ligands and their receptors, the BMP downstream target gene Msx2, which is also necessary and sufficient to promote ICD, was down-regulated in the interdigital regions of Fras1(rdf) hindlimb buds. CONCLUSIONS: The close correlation between limb bud epidermal blistering, decreased Msx2 expression, and reduced ICD in the Fras1(rdf) hindlimb buds suggests 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.
BACKGROUND: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. RESULTS: 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 (Fras1(rdf)). Focusing on the limb, we found that the Fras1(rdf)syndactyly phenotype originates from loss of interdigital cell death (ICD). Despite normal expression of bone morphogenetic protein (BMP) ligands and their receptors, the BMP downstream target gene Msx2, which is also necessary and sufficient to promote ICD, was down-regulated in the interdigital regions of Fras1(rdf) hindlimb buds. CONCLUSIONS: The close correlation between limb bud epidermal blistering, decreased Msx2 expression, and reduced ICD in the Fras1(rdf) hindlimb buds suggests 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.
Authors: Sean M Brugger; Amy E Merrill; Jesus Torres-Vazquez; Nancy Wu; Man-Chun Ting; Jane Y-M Cho; Sonia L Dobias; Soyun E Yi; Karen Lyons; Jeffery R Bell; Kavita Arora; Rahul Warrior; Robert Maxson Journal: Development Date: 2004-10 Impact factor: 6.868
Authors: Lesley McGregor; Ville Makela; Susan M Darling; Sofia Vrontou; Georges Chalepakis; Catherine Roberts; Nicola Smart; Paul Rutland; Natalie Prescott; Jason Hopkins; Elizabeth Bentley; Alison Shaw; Emma Roberts; Robert Mueller; Shalini Jadeja; Nicole Philip; John Nelson; Christine Francannet; Antonio Perez-Aytes; Andre Megarbane; Bronwyn Kerr; Brandon Wainwright; Adrian S Woolf; Robin M Winter; Peter J Scambler Journal: Nat Genet Date: 2003-06 Impact factor: 38.330
Authors: Valerie K Jordan; Tyler F Beck; Andres Hernandez-Garcia; Peter N Kundert; Bum-Jun Kim; Shalini N Jhangiani; Tomasz Gambin; Molly Starkovich; Jaya Punetha; Ingrid S Paine; Jennifer E Posey; Alexander H Li; Donna Muzny; Chih-Wei Hsu; Amber J Lashua; Xin Sun; Caraciolo J Fernandes; Mary E Dickinson; Kevin P Lally; Richard A Gibbs; Eric Boerwinkle; James R Lupski; Daryl A Scott Journal: Hum Mol Genet Date: 2018-06-15 Impact factor: 6.150