title: Syndactyly in a novel Fras1(rdf) mutant results from interruption of signals for interdigital apoptosis.
abstract: 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.affiliation: Laboratory of Genetics University of Wisconsin Madison, WI, 53706.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Hines
authors.affiliation: Laboratory of Genetics University of Wisconsin Madison, WI, 53706.
authors.forename: Jamie M
authors.initials: JM
authors.lastname: Verheyden
authors.affiliation: Laboratory of Genetics University of Wisconsin Madison, WI, 53706.
authors.forename: Amber J
authors.initials: AJ
authors.lastname: Lashua
authors.affiliation: Laboratory of Genetics University of Wisconsin Madison, WI, 53706.
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Larson
authors.affiliation: Laboratory of Genetics University of Wisconsin Madison, WI, 53706.
authors.forename: Kelsey
authors.initials: K
authors.lastname: Branchfield
authors.affiliation: Laboratory of Genetics University of Wisconsin Madison, WI, 53706.
authors.forename: Eric T
authors.initials: ET
authors.lastname: Domyan
authors.affiliation: Institute of Biochemistry and Cell Biology Shanghai Institute for Biological Sciences Chinese Academy of Sciences Shanghai, China, 200031.
authors.forename: Juan
authors.initials: J
authors.lastname: Gao
authors.affiliation: Laboratory of Genetics University of Wisconsin Madison, WI, 53706.
authors.forename: Julie F
authors.initials: JF
authors.lastname: Harvey
authors.affiliation: Laboratory of Genetics University of Wisconsin Madison, WI, 53706.
authors.forename: John C
authors.initials: JC
authors.lastname: Herriges
authors.affiliation: Zhiyuan College Shanghai Jiao Tong University Shanghai, China, 200240.
authors.forename: Linghan
authors.initials: L
authors.lastname: Hu
authors.affiliation: Laboratory of Genetics University of Wisconsin Madison, WI, 53706.
authors.forename: David J
authors.initials: DJ
authors.lastname: Mcculley
authors.affiliation: Laboratory of Genetics University of Wisconsin Madison, WI, 53706.
authors.forename: Kurt
authors.initials: K
authors.lastname: Throckmorton
authors.affiliation: Laboratory of Genetics University of Wisconsin Madison, WI, 53706.
authors.forename: Shigetoshi
authors.initials: S
authors.lastname: Yokoyama
authors.affiliation: Laboratory of Genetics University of Wisconsin Madison, WI, 53706.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Ikeda
authors.affiliation: Institute of Biochemistry and Cell Biology Shanghai Institute for Biological Sciences Chinese Academy of Sciences Shanghai, China, 200031.
authors.forename: Guoliang
authors.initials: G
authors.lastname: Xu
authors.affiliation: Laboratory of Genetics University of Wisconsin Madison, WI, 53706.
authors.forename: Xin
authors.initials: X
authors.lastname: Sun
mesh_terms: D000818:Animals; D017209:Apoptosis; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D006614:Hindlimb / Q000196:embryology* / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D013576:Syndactyly / Q000196:embryology* / Q000235:genetics / Q000473:pathology
chemical_list: D019485:Bone Morphogenetic Proteins; D016326:Extracellular Matrix Proteins; C482018:Fras1 protein, mouse; D018398:Homeodomain Proteins; C084119:MSX2 protein
keywords: BMP signaling; ENU screen; Fraser syndrome; interdigital cell death; limb development
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