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First published online September 1, 2004
doi: 10.1242/10.1242/dev.01327
1 Shriners Hospital for Children, Research Division, Portland, Oregon 97239,
USA
2 Department of Molecular and Medical Genetics, Oregon Health and Science
University, Portland, Oregon 97239, USA
3 Department of Biochemistry and Molecular Biology, Oregon Health and Science
University, Portland, Oregon 97239, USA
Author for correspondence (e-mail:
hss{at}shcc.org)
Accepted 24 June 2004
In humans and mice, loss of HOXA13 function causes defects in the growth and patterning of the digits and interdigital tissues. Analysis of Hoxa13 expression reveals a pattern of localization overlapping with sites of reduced Bmp2 and Bmp7 expression in Hoxa13 mutant limbs. Biochemical analyses identified a novel series of Bmp2 and Bmp7 enhancer regions that directly interact with the HOXA13 DNA-binding domain and activate gene expression in the presence of HOXA13. Immunoprecipitation of HOXA13-Bmp2 and HOXA13-Bmp7 enhancer complexes from the developing autopod confirm that endogenous HOXA13 associates with these regions. Exogenous application of BMP2 or BMP7 partially rescues the Hoxa13 mutant limb phenotype, suggesting that decreased BMP signaling contributes to the malformations present in these tissues. Together, these results provide conclusive evidence that HOXA13 regulates Bmp2 and Bmp7 expression, providing a mechanistic link between HOXA13, its target genes and the specific developmental processes affected by loss of HOXA13 function.
Key words: HOXA13, BMP2, BMP7, Limb, Apoptosis, Gene regulation
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