The multi-chambered mammalian heart arises from a simple tube by polar elongation, myocardial differentiation and morphogenesis. Members of the large family of T-box (Tbx) transcription factors have been identified as crucial players that act in distinct subprogrammes during cardiac regionalization. Tbx1 and Tbx18 ensure elongation of the cardiac tube at the anterior and posterior pole, respectively. Tbx1 acts in the pharyngeal mesoderm to maintain proliferation of mesenchymal precursor cells for formation of a myocardialized and septated outflow tract. Tbx18 is expressed in the sinus venosus region and is required for myocardialization of the caval veins and the sinoatrial node. Tbx5 and Tbx20 function in the early heart tube and independently activate the chamber myocardial gene programme, whereas Tbx2 and Tbx3 locally repress this programme to favour valvuloseptal and conduction system development. Here, we summarize that these T-box factors act in different molecular circuits and control target gene expression using diverse molecular strategies including binding to distinct protein interaction partners.

The compartmentalization of somites along their anterior–posterior (AP) axis is pivotal to the segmental organization of the vertebrate axial skeleton and the peripheral nervous system. Anterior and posterior somite halves contribute to different vertebral elements. They are also characterized by different proliferation rates and properties with respect to neural crest cell migration and spinal nerve passage. AP-somite polarity is generated in the anterior presomitic mesoderm by Mesp2 and Delta/Notch signaling. Here, we demonstrate that maintenance of AP-somite polarity is mediated by the T-box transcription factor Tbx18. Mice deficient for Tbx18 show expansion of pedicles with transverse processes and proximal ribs, elements derived from the posterior lateral sclerotome. AP-somite polarity is established in Tbx18 mutant embryos but is not maintained. During somite maturation, posterior somite compartments expand most likely because of posterior cells invading the anterior somite half. In the anterior lateral sclerotome, Tbx18 acts as an antiapoptotic factor. Ectopic expression experiments suggest that Tbx18 can promote anterior at the expense of posterior somite compartments. In summary, Tbx18 appears to act downstream of Mesp2 and Delta/Notch signaling to maintain the separation of anterior and posterior somite compartments.

Congenital malformations of the urinary tract are a major cause of renal failure in children and young adults. They are often caused by physical obstruction or by functional impairment of the peristaltic machinery of the ureter. The underlying molecular and cellular defects are, however, poorly understood. Here we present the phenotypic characterization of a new mouse model for congenital ureter malformation that revealed the molecular pathway important for the formation of the functional mesenchymal coating of the ureter. The gene encoding the T-box transcription factor Tbx18 was expressed in undifferentiated mesenchymal cells surrounding the distal ureter stalk. In Tbx18^–/– mice, prospective ureteral mesenchymal cells largely dislocalized to the surface of the kidneys. The remaining ureteral mesenchymal cells showed reduced proliferation and failed to differentiate into smooth muscles, but instead became fibrous and ligamentous tissue. Absence of ureteral smooth muscles resulted in a short hydroureter and hydronephrosis at birth. Our analysis also showed that the ureteral mesenchyme derives from a distinct cell population that is separated early in kidney development from that of other mesenchymal cells of the renal system.

A key step in heart development is the coordinated development of the atrioventricular canal (AVC), the constriction between the atria and ventricles that electrically and physically separates the chambers, and the development of the atrioventricular valves that ensure unidirectional blood flow. Using knock-out and inducible overexpression mouse models, we provide evidence that the developmentally important T-box factors Tbx2 and Tbx3, in a functionally redundant manner, maintain the AVC myocardium phenotype during the process of chamber differentiation. Expression profiling and ChIP-sequencing analysis of Tbx3 revealed that it directly interacts with and represses chamber myocardial genes, and induces the atrioventricular pacemaker-like phenotype by activating relevant genes. Moreover, mutant mice lacking 3 or 4 functional alleles of Tbx2 and Tbx3 failed to form atrioventricular cushions, precursors of the valves and septa. Tbx2 and Tbx3 trigger development of the cushions through a regulatory feed-forward loop with Bmp2, thus providing a mechanism for the co-localization and coordination of these important processes in heart development.

After specification of the hepatic endoderm, mammalian liver organogenesis progresses through a series of morphological stages that culminate in the migration of hepatocytes into the underlying mesenchyme to populate the hepatic lobes. Here, we show that in the mouse the transcriptional repressor Tbx3, a member of the T-box protein family, is required for the transition from a hepatic diverticulum with a pseudo-stratified epithelium to a cell-emergent liver bud. In Tbx3-deficient embryos, proliferation in the hepatic epithelium is severely reduced, hepatoblasts fail to delaminate, and cholangiocyte rather than hepatocyte differentiation occurs. Molecular analyses suggest that the primary function of Tbx3 is to maintain expression of hepatocyte transcription factors, including hepatic nuclear factor 4a (Hnf4a) and CCAAT/enhancer binding protein (C/EBP), alpha (Cebpa), and to repress expression of cholangiocyte transcription factors such as Onecut1 (Hnf6) and Hnf1b. Conclusion: Tbx3 controls liver bud expansion by suppressing cholangiocyte and favoring hepatocyte differentiation in the liver bud. (HEPATOLOGY 2009.)