Journal of Pediatric Surgery
Volume 44, Issue 10 , Pages 1904-1912, October 2009

Transcriptional regulation of RET by Nkx2-1, Phox2b, Sox10, and Pax3

Division of Paediatric Surgery, Department of Surgery, The University of Hong Kong, Hong Kong SAR, China

Received 22 October 2008; accepted 25 November 2008.

Abstract 

Background

The rearranged during transfection (RET) gene encodes a single-pass receptor whose proper expression and function are essential for the development of enteric nervous system. Mutations in RET regulatory regions are also associated with Hirschsprung disease (HSCR) (aganglionosis of the colon). We previously showed that 2 polymorphisms in RET promoter are associated with the increased risk of HSCR. These single nucleotide polymorphisms overlap with the NK2 homeobox 1 (Nkx2-1) binding motif interrupting the physical interaction of NKX2-1 with the RET promoter and result in reduced RET transcription. In this study, we further delineated Nkx2-1–mediated RET Transcription.

Methods and results

First, we demonstrated that PHOX2B, like SOX10 and NKX2-1, is expressed in the mature enteric ganglions of human gut by immunohistochemistry. Second, subsequent dual-luciferase-reporter studies indicated that Nkx2-1 indeed works coordinately with Phox2b and Sox10, but not Pax3, to mediate RET transcription. In addition, identification of Phox2b responsive region in RET promoter further provides solid evidence of the potential functional interaction between Phox2b and RET.

Conclusion

In sum, Phox2b and Sox10 act together with Nkx2.1 to modify RET signaling and this interaction may also contribute to HSCR susceptibility.

Key words: RET, Nkx2-1, Phox2b, Transcription

To access this article, please choose from the options below

Login to an existing account or Register a new account.

  • Purchase this article for 31.50 USD (You must login/register to purchase this article)

    Online access for 24 hours. The PDF version can be downloaded as your permanent record.

  • Subscribe to this title

    Get unlimited online access to this article and all other articles in this title 24/7 for one year.

  • Claim access now

    For current subscribers with Society Membership or Account Number.

  • Visit SciVerse ScienceDirect to see if you have access via your institution.
 

PII: S0022-3468(08)01075-0

doi:10.1016/j.jpedsurg.2008.11.055

Journal of Pediatric Surgery
Volume 44, Issue 10 , Pages 1904-1912, October 2009