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Abstract: FR-OR15

The Multimodal Role of TBX6 in Kidney and Urinary Tract Development and Disease

Session Information

Category: Development, Stem Cells, and Regenerative Medicine

  • 600 Development, Stem Cells, and Regenerative Medicine

Authors

  • Whittemore, Gregory Baker, Columbia University Division of Nephrology, New York, New York, United States
  • Martino, Jeremiah, Columbia University Division of Nephrology, New York, New York, United States
  • Gupta, Yask, Columbia University Division of Nephrology, New York, New York, United States
  • Lim, Tze Yin, Columbia University Division of Nephrology, New York, New York, United States
  • Batourina, Ekatherina, Columbia University Department of Urology, New York, New York, United States
  • Liu, Qingxue, Columbia University Division of Nephrology, New York, New York, United States
  • Ke, Juntao, Columbia University Division of Nephrology, New York, New York, United States
  • Sampogna, Rosemary V., Columbia University Division of Nephrology, New York, New York, United States
  • Papaioannou, Virginia E., Columbia University Department of Genetics and Development, New York, New York, United States
  • Mendelsohn, Cathy L., Columbia University Department of Urology, New York, New York, United States
  • Sanna-Cherchi, Simone, Columbia University Division of Nephrology, New York, New York, United States
Background

TBX6 is a transcription factor involved in fate-determination of neuromesoderm precursors (NMP). We recently implicated haploinsufficiency of TBX6 as a driver of the congenital anomalies of the kidney and urinary tract (CAKUT) observed in the chromosome 16p11.2 microdeletion syndrome. Although deletion in mice results in loss of posterior somites and formation of ectopic neural tubes (eNTBs), Tbx6-dependent mechanisms of genitourinary development remain elusive.

Methods

We generated an allelic series from independent null and hypomorphic Tbx6 alleles. We then integrated bulk and single-cell transcriptomics, epigenetics, and transcription factor binding site analysis at E9.5 to identify target tissues and genes. Selected targets were validated by electrophoretic mobility shift assay and in situ hybridization.

Results

We found that severe inactivation of Tbx6 at E9.5 results in a loss of inhibitory control of the Kdm7a promotor, leading to overexpression, driving NMPs to preferentially differentiate into posterior NTB cells and form eNTBs at the expense of intermediate mesoderm (IM). Furthermore, eNTBs likely secrete trophic factors that induce mal-patterning and ectopic positioning of the metanephric mesenchyme (MM). This therefore disrupts the normal interaction of the MM and ureteric bud (UB) required for kidney development resulting in renal agenesis and duplications of the collecting system. Interestingly, less severe Tbx6 inactivation does not yield eNTBs, but still causes renal hypodysplasia and ureteric obstruction. We found this to be due to a loss of Tbx6-dependent activation of the Fgf9 promoter in the IM, leading to a mild depletion of this population.

Conclusion

Here we show spatially and temporally distinct mechanisms whereby Tbx6 influences urinary tract development. Severe inactivation exerts its effect through a Kdm7a-dependent pathway in NMPs, while less severe defects unmask a Kdm7a-independent, Fgf9-dependent effect on the IM. These findings illustrate the importance of spatially and temporally linked gene-dosage on multiorgan development and may also contribute to our understanding of regenerative medicine.

Funding

  • NIDDK Support