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J. Biol. Chem., Vol. 278, Issue 25, 22437-22445, June 20, 2003

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PITX2 Isoform-specific Regulation of Atrial Natriuretic Factor Expression

SYNERGISM AND REPRESSION WITH Nkx2.5^*

Mrudula Ganga , Herbert M. Espinoza , Carol J. Cox , Lisa Morton , Tord A. Hjalt , Youngsook Lee ¶ and Brad A. Amendt  ||

From the Department of Biological Science, The University of Tulsa, Tulsa, Oklahoma 74104-3189, the Department of Cell and Molecular Biology, Lund University, SE-22184 Lund, Sweden, and the ^¶Department of Anatomy, The University of Wisconsin-Madison, Madison, Wisconsin 53706

PITX2 and Nkx2.5 are two of the earliest known transcriptional markers of vertebrate heart development. Pitx2^–/– mice present with severe cardiac malformations and embryonic lethality, demonstrating a role for PITX2 in heart development. However, little is known about the downstream targets of PITX2 in cardiogenesis. We report here that the atrial natriuretic factor (ANF) promoter is a target of PITX2. PITX2A, PITX2B, and PITX2C isoforms differentially activate the ANF promoter. However, only PITX2C can synergistically activate the ANF promoter in the presence of Nkx2.5. We further demonstrate that the procollagen lysyl hydroxylase (PLOD1) promoter is regulated by Nkx2.5. Mechanistically, PITX2C and Nkx2.5 synergistically regulate ANF and PLOD1 expression through binding to their respective DNA elements. Surprisingly, PITX2A activation of the ANF and PLOD1 promoters is repressed by co-transfection of Nkx2.5 in the C3H10T1/2 embryonic fibroblast cell line. Pitx2a and Pitx2c are endogenously expressed in C3H10T1/2 cells, and these cells express factors that differentially regulate PITX2 isoform activities. We provide a new mechanism for the regulation of heart development by PITX2 isoforms through the regulation of ANF and PLOD1 gene expression and Nkx2.5 transcriptional activity.

Received for publication, October 4, 2002 , and in revised form, February 27, 2003.

^* This work was supported by NIDCR, National Institutes of Health Grant 1 RO1 DE13941 and American Heart Association Grant 9960299Z (to B. A. A.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Dept. of Biological Sciences, The University of Tulsa, 600 S. College Ave., Tulsa, OK 74104-3189. Tel.: 918-631-3328; Fax: 918-631-2762; E-mail: bradamendt{at}utulsa.edu.

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