Kidney Week

Abstract: TH-OR084

TFAP2A Is a Novel Regulator of Renal Progenitor Fate during Kidney Ontogeny

Session Information

• Novel Mechanisms and Pathways in Kidney Development
  November 02, 2017 | Location: Room 385, Morial Convention Center
  Abstract Time: 05:42 PM - 05:54 PM

Category: Developmental Biology and Inherited Kidney Diseases

• 401 Developmental Biology

Authors

• Chambers, Brooke E., University of Notre Dame, Notre Dame, Indiana, United States

Brooke E. Chambers, PhD

• Wingert, Rebecca A., University of Notre Dame, Notre Dame, Indiana, United States

Rebecca A. Wingert,

Background

Occurring in 1 in 500 births, Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) are the primary cause of pediatric end-stage renal disease. The central etiology of these conditions involves aberrant development of nephrons, which are the functional units of the kidney.

Methods

Zebrafish have emerged as a powerful genetic system to study the molecular coordination of cell fate decisions during vertebrate nephron formation. Here, through a forward ENU screen, we isolated a nephron mutant with abrogated distal tubules. Whole genome sequencing revealed a lesion that disrupts splicing of transcription factor AP-2 alpha (tfap2a), thereby truncating essential transcriptional activation and DNA binding domains. Until now, tfap2a has been known as essential for neural crest and epidermis differentiation but was not appreciated to act during renal ontogeny.

Results

We found that tfap2a was dynamically expressed in zebrafish renal progenitors, eventually restricting to the distal tubules. During mouse embryogenesis, tfap2a expression was abundant within the developing urogenital tract encompassing structures such as the ureteric tip and distal tubules. Human tfap2a mutations result in branchio-oculo-facial syndrome (BOFS), which primarily affects craniofacial tissue, though case reports have linked tfap2a lesions to multicystic dysplastic kidney. Complementation tests between our mutant line and tfap2a^m819, which encodes a nonsense allele, as well as knockdown studies similarly abolished the distal tubule. Conversely, overexpression of tfap2a caused a striking expansion of distal cells. Through a subsequent suite of functional studies, we have determined that tfap2a acts upstream of several key lineage factors necessary for distal tubule formation, like the T-box transcription factor tbx2b. In addition, our data suggests tfap2a interplays with Iroquois homeobox genes irx1a and irx3b to pattern distal nephron structures.

Conclusion

Taken together, our studies have revealed novel mechanisms by which tfap2a directs cell fate during nephrogenesis. Examining the molecular activities of this conserved transcription factor in renal progenitors will shed light on the regulatory role of the mammalian homologue, AP-2α, in congenital diseases.

Funding

• NIDDK Support