title: Sost and its paralog Sostdc1 coordinate digit number in a Gli3-dependent manner.
abstract: WNT signaling is critical in most aspects of skeletal development and homeostasis, and antagonists of WNT signaling are emerging as key regulatory proteins with great promise as therapeutic agents for bone disorders. Here we show that Sost and its paralog Sostdc1 emerged through ancestral genome duplication and their expression patterns have diverged to delineate non-overlapping domains in most organ systems including musculoskeletal, cardiovascular, nervous, digestive, reproductive and respiratory. In the developing limb, Sost and Sostdc1 display dynamic expression patterns with Sost being restricted to the distal ectoderm and Sostdc1 to the proximal ectoderm and the mesenchyme. While Sostdc1(-/-) mice lack any obvious limb or skeletal defects, Sost(-/-) mice recapitulate the hand defects described for Sclerosteosis patients. However, elevated WNT signaling in Sost(-/-); Sostdc1(-/-) mice causes misregulation of SHH signaling, ectopic activation of Sox9 in the digit 1 field and preaxial polydactyly in a Gli1- and Gli3-dependent manner. In addition, we show that the syndactyly documented in Sclerosteosis is present in both Sost(-/-) and Sost(-/-); Sostdc1(-/-) mice, and is driven by misregulation of Fgf8 in the AER, a region lacking Sost and Sostdc1 expression. This study highlights the complexity of WNT signaling in skeletal biology and disease and emphasizes how redundant mechanism and non-cell autonomous effects can synergize to unveil new intricate phenotypes caused by elevated WNT signaling.
authors.affiliation: Biology and Biotechnology Division, Lawrence Livermore National Laboratory, 7000 East Avenue, L-452, Livermore, CA 94550, USA.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Collette
authors.forename: Cristal S
authors.initials: CS
authors.lastname: Yee
authors.forename: Deepa
authors.initials: D
authors.lastname: Murugesh
authors.forename: Aimy
authors.initials: A
authors.lastname: Sebastian
authors.forename: Leila
authors.initials: L
authors.lastname: Taher
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Gale
authors.forename: Aris N
authors.initials: AN
authors.lastname: Economides
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 / Q000235:genetics / Q000378:metabolism*; D019295:Computational Biology; D004475:Ectoderm / Q000196:embryology* / Q000378:metabolism; D019143:Evolution, Molecular; D005121:Extremities / Q000196:embryology*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000378:metabolism; D017403:In Situ Hybridization; D036341:Intercellular Signaling Peptides and Proteins; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D046228:Microarray Analysis; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D055758:SOX9 Transcription Factor / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000502:physiology*; D000074290:Zinc Finger Protein Gli3
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019485:Bone Morphogenetic Proteins; C465571:Gli3 protein, mouse; D006023:Glycoproteins; D053823:Hedgehog Proteins; D036341:Intercellular Signaling Peptides and Proteins; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D055758:SOX9 Transcription Factor; C486030:Sost protein, mouse; C483887:Sostdc1 protein, mouse; C527933:Sox9 protein, mouse; D000074290:Zinc Finger Protein Gli3
keywords: Limb formation; Polydactyly; Sclerostin; Shh; Sost; Sostdc1; WNT signaling; syndactyly