A mouse model for human short-stature syndromes identifies Shox2 as an upstream regulator of Runx2 during long-bone development

Abstract

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.limb ͉ SHOX

Development of the Endochondral Skeleton

“…The transcription factors FoxA2 and FoxA3 are necessary for chondrocyte hypertrophy (Ionescu et al 2012). SHOX2, a homeodomain-containing transcription factor, is necessary for RUNX2/RUNX3 expression and hypertrophy within the stylopod (see Box 1) (Cobb et al 2006;Yu et al 2007). Finally, Zfp521, a zinc finger-containing transcriptional coregulator, suppresses chondrocyte hypertrophy and partly mediates the function of PTHrP in this process Seriwatanachai et al 2011).…”

Genetic Interactions Between Shox2 and Hox Genes During the Regional Growth and Development of the Mouse Limb

“…Mouse lines used were Shox2 fl/+ (Cobb et al 2006), Rosa CAG-STOP-Shox2 (Scott et al 2011), HoxD +/2 (Del9) (Spitz et al 2001), HoxA fl/+ (Kmita et al 2005), and Prrx1-Cre (Logan et al 2002). The Life and Environmental Sciences Animal Care Committee approved all animal experiments.…”

“…In humans, loss of SHOX leads to the truncated zeugopod elements found in people with LeriWeill, Turner, and Langer syndromes (Rao et al 1997;Belin et al 1998;Shears et al 1998;Zinn et al 2002). While rodents have uniquely lost the Shox gene among mammals (Gianfrancesco et al 2001), disruption of the widely conserved Shox2 gene results in severely shortened stylopodal elements in mice (Cobb et al 2006). Thus, Hox and Shox gene perturbations each give rise to regional phenotypes along the proximodistal axis, suggesting the possibility that these genes function together during limb development.…”

“…The reported expression of human SHOX and SHOX2 is also regional, with SHOX2 expressed in the developing stylopod and SHOX expressed in the developing zeugopod (ClementJones et al 2000). Mouse Shox2 expression, in contrast, occupies both the developing stylopodal and zeugopodal domains even though its mutation primarily disrupts the developing stylopod (Cobb et al 2006). Within their broad segmental domains, Shox2 and at least some Hox genes are expressed in the proliferating chondrocytes and perichondrium of developing skeletal elements (Villavicencio-Lorini et al 2010;Swinehart et al 2013), being thus associated with their continual growth during development.…”

“…Runx2, which is expressed both by chondrocytes and the perichondrium, is essential for proper chondrocyte hypertrophy and the formation of osteoblasts, thus being important for both the proper development of the cartilage template and its eventual replacement by bone (Otto et al 1997;Yoshida et al 2004). As mutation of Shox2 or Hox genes results in a strong reduction or loss of Runx2 expression, a lack of chondrocyte maturation likely underlies regional shortening in these animals (Boulet and Capecchi 2004;Cobb et al 2006;Villavicencio-Lorini et al 2010;Gross et al 2012). The regulation of individual Hox and Shox genes follows precise spatial and temporal patterns of gene expression in the limb.…”