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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:
 [1];  [2];  [1];  [3];  [1]
  1. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Univ. of California, Berkeley, CA (United States)
  2. Univ. of California, Davis, CA (United States)
  3. Univ. of California, Berkeley, CA (United States)
Publication Date:
Research Org.:
Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)
Sponsoring Org.:
USDOE National Nuclear Security Administration (NNSA)
OSTI Identifier:
1839869
Report Number(s):
LLNL-JRNL-408192
Journal ID: ISSN 0012-1606; 366998
Grant/Contract Number:  
AC52-07NA27344
Resource Type:
Accepted Manuscript
Journal Name:
Developmental Biology
Additional Journal Information:
Journal Volume: 342; Journal Issue: 2; Journal ID: ISSN 0012-1606
Publisher:
Elsevier
Country of Publication:
United States
Language:
English
Subject:
Biological and medical sciences; WNT signaling; SOST; Sclerostin; Shh; Limb formation

Citation Formats

Collette, Nicole M., Genetos, Damian C., Murugesh, Deepa, Harland, Richard M., and Loots, Gabriela G. Genetic evidence that SOST inhibits WNT signaling in the limb. United States: N. p., 2010. Web. doi:10.1016/j.ydbio.2010.03.021.
Collette, Nicole M., Genetos, Damian C., Murugesh, Deepa, Harland, Richard M., & Loots, Gabriela G. Genetic evidence that SOST inhibits WNT signaling in the limb. United States. https://doi.org/10.1016/j.ydbio.2010.03.021
Collette, Nicole M., Genetos, Damian C., Murugesh, Deepa, Harland, Richard M., and Loots, Gabriela G. Tue . "Genetic evidence that SOST inhibits WNT signaling in the limb". United States. https://doi.org/10.1016/j.ydbio.2010.03.021. https://www.osti.gov/servlets/purl/1839869.
@article{osti_1839869,
title = {Genetic evidence that SOST inhibits WNT signaling in the limb},
author = {Collette, Nicole M. and Genetos, Damian C. and Murugesh, Deepa and Harland, Richard M. and Loots, Gabriela G.},
abstractNote = {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.},
doi = {10.1016/j.ydbio.2010.03.021},
journal = {Developmental Biology},
number = 2,
volume = 342,
place = {United States},
year = {Tue Mar 30 00:00:00 EDT 2010},
month = {Tue Mar 30 00:00:00 EDT 2010}
}

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