Abstract
The homeobox gene SHOX encodes for a transcription factor that plays an important role during limb development. Mutations or deletions of SHOX in humans cause short stature in Turner, Langer and Leri-Weill syndrome as well as idiopathic short stature. During embryonic development, SHOX is expressed in a complex spatio-temporal pattern that requires the presence of specific regulatory mechanisms. Up to now, it was known that SHOX is regulated by two upstream promoters and several enhancers on either side of the gene, but no regulators have been identified that can activate or repress the transcription of SHOX by binding to these regulatory elements. We have now identified the homeodomain protein HOXA9 as a positive regulator of SHOX expression in U2OS cells. Using luciferase assays, chromatin immunoprecipitation and electrophoretic mobility shift assays, we could narrow down the HOXA9 binding site to two AT-rich sequences of 31 bp within the SHOX promoter 2. Virus-induced Hoxa9 overexpression in a chicken micromass model validated the regulation of Shox by Hoxa9 (negative regulation). As Hoxa9 and Shox are both expressed in overlapping regions of the developing limb buds, a regulatory relationship of Hoxa9 and Shox during the process of limb development can be assumed.
Highlights
The human pseudoautosomal gene SHOX encodes for a homeodomain transcription factor with a crucial role during limb development and growth regulation [1,2,3]
To identify potential transcription factors that can bind to SHOX regulatory elements, we carried out in silico transcription factor binding site predictions using MatInspector (Genomatix Software GmbH) [18,19]
The homeobox gene SHOX is known to play a key role during limb development, and mutations or deletions lead to the limb malformations seen in LWD and Langer syndrome or to short stature without limb anomalies in patients with idiopathic short stature [3,4,5,33]
Summary
The human pseudoautosomal gene SHOX encodes for a homeodomain transcription factor with a crucial role during limb development and growth regulation [1,2,3]. Mutations or deletions of SHOX have been identified as the primary cause of several disorders characterized by reduced body height and skeletal deformities including the short stature associated with Turner Syndrome, Leri-Weill Dyschondrosteosis and Langer Syndrome [4,5] In these syndromes, the skeletal malformations manifest as a mesomelic shortening of the long bones of the limbs, affecting the middle portion of the upper limbs, where a shortening and bowing of the radius leads to a dorsal subluxation of the ulna (Madelung deformity). The SHOX protein was detected in the chondrocytes of fetal and childhood growth plates [7,8] These observations have implied a role of SHOX in bone development and offer an explanation for the localized symptoms seen in SHOX-deficient patients
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