title: Brachy-syndactyly caused by loss of Sfrp2 function.
abstract: Wnt signaling pathways are regulated both at the intracellular and extracellular levels. During embryogenesis, the in vivo effects of the secreted frizzled-related protein (Sfrp) family of Wnt inhibitors are poorly understood. Here, we show that inactivation of Sfrp2 results in subtle limb defects in mice with mesomelic shortening and consistent shortening of all autopodal elements that is clinically manifested as brachydactyly. In addition, there is soft-tissue syndactyly of the hindlimb. The brachydactyly is caused by decreased chondrocyte proliferation and delayed differentiation in distal limb chondrogenic elements. These data suggest that Sfrp2 can regulate both chondrogenesis and regression of interdigital mesenchyme in distal limb. Sfrp2 can also repress canonical Wnt signaling by Wnt1, Wnt9a, and Wnt4 in vitro. Sfrp2-/- and TOPGAL/Sfrp2-/- mice have a mild increase in beta-catenin and beta-galactosidase staining, respectively, in some phalangeal elements. This however does not exclude a potential concurrent effect on non-canonical Wnt signaling in the growth plate. In combination with what is known about BMP and Wnt signaling in human brachydactylies, our data establish a critical role for Sfrp2 in proper distal limb formation and suggest SFPR2 could be a novel candidate gene for human brachy-syndactyly defects.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA. rmorello@bcm.edu
authors.forename: Roy
authors.initials: R
authors.lastname: Morello
authors.forename: Terry K
authors.initials: TK
authors.lastname: Bertin
authors.forename: Silke
authors.initials: S
authors.lastname: Schlaubitz
authors.forename: Chad A
authors.initials: CA
authors.lastname: Shaw
authors.forename: Sujatha
authors.initials: S
authors.lastname: Kakuru
authors.forename: Elda
authors.initials: E
authors.lastname: Munivez
authors.forename: Pia
authors.initials: P
authors.lastname: Hermanns
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Chen
authors.forename: Bernhard
authors.initials: B
authors.lastname: Zabel
authors.forename: Brendan
authors.initials: B
authors.lastname: Lee
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015152:Blotting, Northern; D001842:Bone and Bones / Q000002:abnormalities*; D002356:Cartilage / Q000002:abnormalities*; D002454:Cell Differentiation; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism; D020219:Chondrogenesis / Q000502:physiology; D005121:Extremities / Q000196:embryology*; D015870:Gene Expression; D018507:Gene Expression Regulation, Developmental; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D016133:Polymerase Chain Reaction; D013576:Syndactyly / Q000209:etiology*; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D008565:Membrane Proteins; C491628:Sfrp2 protein, mouse; D000094742:Secreted Frizzled-Related Proteins