A mouse model for human short-stature syndromes identifies Shox2 as an upstream regulator of Runx2 during long-bone development.
Deficiencies or mutations in the human pseudoautosomal SHOX gene are associated with a series of short-stature conditions, including Turner syndrome, Leri-Weill dyschondrosteosis, and Langer mesomelic dysplasia. Although this gene is absent from the mouse genome, the closely related paralogous gene Shox2 displays a similar expression pattern in developing limbs. Here, we report that the conditional inactivation of Shox2 in developing appendages leads to a strong phenotype, similar to the human conditions, although it affects a different proximodistal limb segment. Furthermore, using this mouse model, we establish the cellular etiology of these defects and show that Shox2 acts upstream the Runx2 gene, a key regulator of chondrogenesis.
Cobb
John
J
Department of Zoology and Animal Biology and National Research Center Frontiers in Genetics, Sciences III, University of Geneva, Quai Ernest Ansermet 30, 1211 Geneva 4, Switzerland.
Dierich
Andrée
A
Huss-Garcia
Yolande
Y
Duboule
Denis
D
D000818:Animals; D001846:Bone Development / Q000235:genetics; D001842:Bone and Bones / Q000002:abnormalities; D019902:Chondrocytes / Q000737:chemistry / Q000378:metabolism; D020219:Chondrogenesis / Q000235:genetics*; D050659:Core Binding Factor Alpha 1 Subunit / Q000032:analysis / Q000235:genetics*; D004195:Disease Models, Animal; D018507:Gene Expression Regulation, Developmental; D006130:Growth Disorders / Q000235:genetics* / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D017880:Limb Deformities, Congenital / Q000235:genetics / Q000473:pathology; D051379:Mice / Q000235:genetics*; D008817:Mice, Mutant Strains; D010641:Phenotype; D017384:Sequence Deletion; D013577:Syndrome
D050659:Core Binding Factor Alpha 1 Subunit; D018398:Homeodomain Proteins; C493716:Runx2 protein, mouse; C484663:Shox2 protein, mouse