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Regulation of c-Ret in the developing kidney is responsive to Pax2 gene dosage

Jason C Clarke1, Sanjeevkumar R Patel, Richard M Raymond

  • 1Department of Pediatrics, University of Michigan, Ann Arbor 48109, USA, and Kolling Institute, Royal North Shore Hospital, St Leonards, Sydney, New South Wales, Australia.

Human Molecular Genetics
|October 19, 2006
PubMed

Insights

Pax2 is crucial for kidney development by regulating the Ret/Gdnf pathway. This transcription factor activates gene expression for the Ret receptor and Gdnf ligand, ensuring proper kidney formation.

Area of Science:

  • Developmental Biology
  • Genetics
  • Molecular Biology

Background:

  • Pax2 and Pax8 are early markers in mammalian kidney development.
  • The Ret/Gdnf pathway is essential for renal development.
  • Pax2 expression precedes c-Ret, suggesting a regulatory relationship.

Purpose of the Study:

  • To investigate the role of Pax2 in regulating c-Ret expression during kidney development.
  • To determine if Pax2 directly interacts with the c-RET promoter.
  • To analyze the impact of reduced Pax2 gene dosage on the Ret/Gdnf pathway and kidney development.

Main Methods:

  • In vitro studies using reporter gene assays to assess promoter activity.
  • Analysis of Pax2-/- mutant mice for c-Ret expression.
  • Generation and analysis of compound heterozygous Pax2+/-: Ret+/- mice.
  • Real-time quantitative RT-PCR to measure Gdnf and c-Ret expression levels.

Main Results:

  • Pax2 protein interacts with the c-RET promoter and activates its expression.
  • Pax2 deficiency leads to loss of c-Ret expression in developing kidneys.
  • Pax2+/-: Ret+/- mice exhibit renal agenesis and reduced nephron number.
  • Reduced Pax2 gene dosage significantly decreases Gdnf and c-Ret expression.

Conclusions:

  • Pax2 is essential for initiating and maintaining the Ret/Gdnf pathway in kidney development.
  • Pax2 acts as a transcriptional activator for both the Ret receptor and Gdnf ligand.
  • Reduced Pax2 levels result in haploinsufficiency, amplifying developmental defects through the Ret/Gdnf pathway.

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