Journal Article

SHOX interacts with the chondrogenic transcription factors SOX5 and SOX6 to activate the aggrecan enhancer

Miriam Aza-Carmona, Debbie J. Shears, Patricia Yuste-Checa, Verónica Barca-Tierno, Alfonso Hisado-Oliva, Alberta Belinchón, Sara Benito-Sanz, J. Ignacio Rodríguez, Jesús Argente, Ángel Campos-Barros, Peter J. Scambler and Karen E. Heath

in Human Molecular Genetics

Volume 20, issue 8, pages 1547-1559
Published in print April 2011 | ISSN: 0964-6906
Published online January 2011 | e-ISSN: 1460-2083 | DOI:

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SHOX (short stature homeobox-containing gene) encodes a transcription factor implicated in skeletal development. SHOX haploinsufficiency has been demonstrated in Leri–Weill dyschondrosteosis (LWD), a skeletal dysplasia associated with disproportionate short stature, as well as in a variable proportion of cases with idiopathic short stature (ISS). In order to gain insight into the SHOX signalling pathways, we performed a yeast two-hybrid screen to identify SHOX-interacting proteins. Two transcription factors, SOX5 and SOX6, were identified. Co-immunoprecipitation assays confirmed the existence of the SHOX–SOX5 and SHOX–SOX6 interactions in human cells, whereas immunohistochemical studies demonstrated the coexpression of these proteins in 18- and 32-week human fetal growth plates. The SHOX homeodomain and the SOX6 HMG domain were shown to be implicated in the SHOX–SOX6 interaction. Moreover, different SHOX missense mutations, identified in LWD and ISS patients, disrupted this interaction. The physiological importance of these interactions was investigated by studying the effect of SHOX on a transcriptional target of the SOX trio, Agc1, which encodes one of the main components of cartilage, aggrecan. Our results show that SHOX cooperates with SOX5/SOX6 and SOX9 in the activation of the upstream Agc1 enhancer and that SHOX mutations affect this activation. In conclusion, we have identified SOX5 and SOX6 as the first two SHOX-interacting proteins and have shown that this interaction regulates aggrecan expression, an essential factor in chondrogenesis and skeletal development.

Journal Article.  7242 words.  Illustrated.

Subjects: Genetics and Genomics