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Published on: February 9, 2017
Spatiotemporal switch from DeltaNp73 to TAp73 isoforms during nephrogenesis: impact on differentiation gene
Zubaida Saifudeen1, Virginia Diavolitsis, Jana Stefkova
1Department of Pediatrics, Section of Pediatric Nephrology, Tulane University Health Sciences Center, New Orleans, Louisiana 70112, USA.
Abstract:
p73 is a member of the p53 gene family, which also includes p53 and p63. These proteins share sequence similarity and target genes but also have divergent roles in cancer and development. Unlike p53, transcription of the p73 gene yields multiple full-length (transactivation (TA) domain) and amino terminus-truncated (DeltaN) isoforms. DeltaNp73 acts in a dominant negative fashion to inhibit the actions of TAp73 and p53 on their target genes, promoting cell survival and proliferation and suppressing apoptosis. The balance between TAp73 and its negative regulator, DeltaNp73, may therefore represent an important determinant of developmental cell fate. There is little if anything known regarding the developmental regulation of the p73 gene. In this study, we showed that TAp73 and DeltaNp73 exhibit reciprocal spatiotemporal expression and functions during nephrogenesis. TAp73 was predominantly expressed in the differentiation domain of the renal cortex in an overlapping manner with the vasopressin-sensitive water channel aquaporin-2 (AQP-2). Chromatin immunoprecipitation assays demonstrated that the endogenous AQP-2 promoter was occupied by TAp73 in a developmentally regulated manner. Furthermore TAp73 stimulated AQP-2 promoter-driven reporter expression. TAp73 also activated the bradykinin B2 receptor (B2R) promoter, a developmentally regulated gene involved in regulation of sodium excretion. The transcriptional effects of TAp73 on AQP-2 and B2R were independent of p53. In marked contrast to TAp73, DeltaNp73 isoforms were induced early in development and were preferentially expressed in proliferating nephron precursors. Moreover DeltaNp73 was a potent repressor of B2R gene transcription. We conclude that the p73 gene is developmentally regulated during kidney organogenesis. The spatiotemporal switch from DeltaNp73 to TAp73 may play an important role in the terminal differentiation program of the developing nephron.
Insights
The p73 gene
Area of Science:
- Molecular Biology
- Developmental Biology
- Genetics
Background:
- The p73 gene, part of the p53 family, has distinct roles in development and cancer.
- p73 produces full-length (TAp73) and truncated (DeltaNp73) isoforms with opposing functions.
- DeltaNp73 inhibits TAp73 and p53, promoting cell survival and proliferation.
Purpose of the Study:
- To investigate the developmental regulation of the p73 gene during kidney organogenesis.
- To elucidate the distinct roles of TAp73 and DeltaNp73 isoforms in nephrogenesis.
- To determine the impact of p73 isoforms on the expression of key developmental genes.
Main Methods:
- Analyzing spatiotemporal expression patterns of TAp73 and DeltaNp73 during kidney development.
- Utilizing chromatin immunoprecipitation assays to assess TAp73 binding to target gene promoters.
- Employing reporter assays to measure the transcriptional activity of TAp73 and DeltaNp73 on specific promoters.
Main Results:
- TAp73 and DeltaNp73 exhibit reciprocal expression patterns during nephrogenesis.
- TAp73 is expressed in differentiating nephron segments and activates aquaporin-2 (AQP-2) and bradykinin B2 receptor (B2R) promoters.
- DeltaNp73 is expressed in proliferating precursors and represses B2R transcription, independent of p53.
Conclusions:
- The p73 gene is developmentally regulated during kidney organogenesis.
- A switch from DeltaNp73 to TAp73 expression is crucial for nephron terminal differentiation.
- Reciprocal functions of p73 isoforms orchestrate kidney development.
