title: Genetic evidence that SOST inhibits WNT signaling in the limb.
abstract: SOST is a negative regulator of bone formation, and mutations in human SOST are responsible for sclerosteosis. In addition to high bone mass, sclerosteosis patients occasionally display hand defects, suggesting that SOST may function embryonically. Here we report that overexpression of SOST leads to loss of posterior structures of the zeugopod and autopod by perturbing anterior-posterior and proximal-distal signaling centers in the developing limb. Mutant mice that overexpress SOST in combination with Grem1 and Lrp6 mutations display more severe limb defects than single mutants alone, while Sost(-/-) significantly rescues the Lrp6(-/-) skeletal phenotype, signifying that SOST gain-of-function impairs limb patterning by inhibiting the WNT signaling through LRP5/6.
authors.affiliation: Biology and Biotechnology Division, Lawrence Livermore National Laboratory, Livermore, CA 94550, USA.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Collette
authors.forename: Damian C
authors.initials: DC
authors.lastname: Genetos
authors.forename: Deepa
authors.initials: D
authors.lastname: Murugesh
authors.forename: Richard M
authors.initials: RM
authors.lastname: Harland
authors.forename: Gabriela G
authors.initials: GG
authors.lastname: Loots
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D005121:Extremities / Q000196:embryology*; D005819:Genetic Markers; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D051153:Wnt Proteins / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019485:Bone Morphogenetic Proteins; D005819:Genetic Markers; C422903:SOST protein, human; D051153:Wnt Proteins