Tbx18 expression demarcates multipotent precursor populations in the developing urogenital system but is exclusively required within the ureteric mesenchymal lineage to suppress a renal stromal fate

Abstract

The mammalian urogenital system derives from multipotent progenitor cells of different germinal tissues. The contribution of individual sub-populations to specific components of the mature system, and the spatiotemporal restriction of the respective lineages have remained poorly characterized. Here, we use comparative expression analysis to delineate sub-regions within the developing urogenital system that express the T-box transcription factor gene Tbx18. We show that Tbx18 is transiently expressed in the epithelial lining and the subjacent mesenchyme of the urogenital ridge. At the onset of metanephric development Tbx18 expression occurs in a band of mesenchyme in between the metanephros and the Wolffian duct but is subsequently restricted to the mesenchyme surrounding the distal ureter stalk. Genetic lineage tracing reveals that former Tbx18(+) cells of the urogenital ridge and the metanephric field contribute substantially to the adrenal glands and gonads, to the kidney stroma, the ureteric and the bladder mesenchyme. Loss of Tbx18 does not affect differentiation of the adrenal gland, the gonad, the bladder and the kidney. However, ureter differentiation is severely disturbed as the mesenchymal lineage adopts a stromal rather than a ureteric smooth muscle fate. DiI labeling and tissue recombination experiments show that the restriction of Tbx18 expression to the prospective ureteric mesenchyme does not reflect an active condensation process but is due to a specific loss of Tbx18 expression in the mesenchyme out of range of signals from the ureteric epithelium. These cells either contribute to the renal stroma or undergo apoptosis aiding in severing the ureter from its surrounding tissues. We show that Tbx18-deficient cells do not respond to epithelial signals suggesting that Tbx18 is required to prepattern the ureteric mesenchyme. Our study provides new insights into the molecular diversity of urogenital progenitor cells and helps to understand the specification of the ureteric mesenchymal sub-lineage.

Pbx1 dependent control of VMC differentiation kinetics underlies gross renal vascular patterning

“…As expected, Pbx1 levels were not perturbed in Pax2 + nephron progenitors or ureteral mesenchyme, which derive from distinct Six2 and Tbx18 lineages, respectively (supplementary material Fig. S2I,J) (Kobayashi et al, 2008;Bohnenpoll et al, 2013).…”

Mutations in TBX18 Cause Dominant Urinary Tract Malformations via Transcriptional Dysregulation of Ureter Development

“…As a consequence, the renal pelvis becomes dramatically enlarged at the expense of the ureter, and hydronephrosis develops at birth. 22,23 We show by immunohistochemistry that TBX18 localizes to the renal pelvic and ureteral smooth muscle cells ( Figure S3). …”

The T-box gene family: emerging roles in development, stem cells and cancer

“…However, the significance of dimerization was called into question by subsequent studies of TBX3 and TBX1 bound to the palindromic consensus sequence, as the dimerization interface in this context is arguably too small to constitute a biologically relevant protein interface, and the proteins Table 1. Major developmental effects of heterozygosity, homozygosity and tissue-specific mutation of T-box genes in mouse with the corresponding human developmental syndrome and phenotypes Airik et al, 2006;Bohnenpoll et al, 2013;Bussen et al, 2004;Greulich et al, 2011;Norden et al, 2012;Trowe et al, 2008 Tbx20 Viable, heart contractile function defects, cardiomyopathy…”