HOXA13 regulates the expression of bone morphogenetic proteins 2 and 7 to control distal limb morphogenesis.
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.
Knosp
Wendy M
WM
Shriners Hospital for Children, Research Division, Portland, Oregon 97239, USA.
Scott
Virginia
V
Bächinger
Hans Peter
HP
Stadler
H Scott
HS
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D055396:Bone Morphogenetic Protein 2; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000235:genetics*; D002460:Cell Line; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004742:Enhancer Elements, Genetic / Q000235:genetics; D005121:Extremities / Q000196:embryology*; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006720:Homozygote; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009024:Morphogenesis / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D016415:Sequence Alignment; D016212:Transforming Growth Factor beta / Q000235:genetics*
C525718:BMP2 protein, human; C525819:BMP7 protein, human; C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D018398:Homeodomain Proteins; D016212:Transforming Growth Factor beta; C099959:homeobox protein HOXA13; D004247:DNA