Tbx4 interacts with the short stature homeobox gene Shox2 in limb development. Issue 5 (28th January 2014)

• Record Type: Journal Article
• Authors: Glaser, Anne; Arora, Ripla; Hoffmann, Sandra; Li, Li; Gretz, Norbert; Papaioannou, Virginia E.; Rappold, Gudrun A.
• Is Part Of: Developmental dynamics. Volume 243:Issue 5(2014:May)
• Page Start: 629
• Page End: 639
• Publication Date: 2014-01-28
• Subjects: Morphogenesis -- Periodicals; Anatomy -- Periodicals; Anatomie -- Périodiques; Biologie du développement -- Périodiques; 571.833
• DOI: 10.1002/dvdy.24104
• Languages: English
• ISSNs: 1058-8388

Abstract

<abstract abstract-type="main"> <title>ABSTRACT</title> <p> <underline>Background:</underline> The short stature homeodomain transcription factors SHOX and SHOX2 play key roles in limb formation. To gain more insight into genes regulated by Shox2 during limb development, we analyzed expression profiles of WT and <italic>Shox2</italic><sup>−/−</sup> mouse embryonic limbs and identified the T‐Box transcription factor Tbx4 as a potential downstream target. Tbx4 is known to exert essential functions in skeletal and muscular hindlimb development. In humans, haploinsufficiency of <italic>TBX4</italic> causes small patella syndrome, a skeletal dysplasia characterized by anomalies of the knee, pelvis, and foot. <underline>Results:</underline> Here, we demonstrate an inhibitory regulatory effect of Shox2 on <italic>Tbx4</italic> specifically in the forelimbs. We also show that Tbx4 activates <italic>Shox2</italic> expression in fore‐ and hindlimbs, suggesting Shox2 as a feedback modulator of Tbx4. Using EMSA studies, we find that Tbx4/TBX4 is able to bind to distinct T‐box binding sites within the mouse and human <italic>Shox2/SHOX2</italic> promoter. <underline>Conclusions:</underline> Our data identifies Tbx4 as a novel transcriptional activator of <italic>Shox2</italic> during murine fore‐ and hindlimb development. <italic>Tbx4</italic> is also regulated by Shox2 specifically in the forelimb bud possibly via a feedback mechanism. These data extend our understanding of the role and regulation of Tbx4 and Shox2 in limb development and limb associated diseases. <italic>Developmental Dynamics 243:629–639, 2014</italic>. © 2013 Wiley Periodicals, Inc.</p> </abstract>