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J. Biol. Chem., Vol. 283, Issue 17, 11841-11849, April 25, 2008

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HIF-1 Signaling Upstream of NKX2.5 Is Required for Cardiac Development in Xenopus^*

Kaori Nagao, Yoshiaki Taniyama, Thomas Kietzmann, Takefumi Doi^¶, Issei Komuro^¶, and Ryuichi Morishita¹

From the Departments of Clinical Gene Therapy and ^¶Pharmacology, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan, the Department of Biochemistry, University of Kaiserslautern, Erwin-Schrödinger-Str. 54, 67663 Kaiserslautern, Germany, and the ^¶Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan

HIF-1 is originally identified as a transcription factor that activates gene expression in response to hypoxia. In metazoans, HIF-1 functions as a master regulator of oxygen homeostasis and regulates adaptive responses to change in oxygen tension during embryogenesis, tissue ischemia, and tumorigenesis. Because Hif-1-deficient mice exhibit a number of developmental defects, the precise role of HIF-1 in early cardiac morphogenesis has been uncertain. Therefore, to clarify the role of HIF-1 in heart development, we investigated the effect of knockdown of HIF-1 in Xenopus embryos using antisense morpholino oligonucleotide microinjection techniques. Knockdown of HIF-1 resulted in defects of cardiogenesis. Whole mount in situ hybridization for cardiac troponin I (cTnI) showed the two separated populations of cardiomyocytes, which is indicative of cardia bifida, in HIF-1-depleted embryos. Furthermore, the depletion of HIF-1 led to the reduction in cTnI expression, suggesting the correlation between HIF-1 and cardiac differentiation. We further examined the expression of several heart markers, nkx2.5, gata4, tbx5, bmp4, hand1, and hand2 in HIF-1-depleted embryos. Among them, the expression of nkx2.5 was significantly reduced. Luciferase reporter assay using the Nkx2.5 promoter showed that knockdown of HIF-1 decreased its promoter activity. The cardiac abnormality in the HIF-1-depleted embryo was restored with co-injection of nkx2.5 mRNA. Collectively, these findings reveal that HIF-1-regulated nkx2.5 expression is required for heart development in Xenopus.

Received for publication, March 26, 2007 , and in revised form, February 21, 2008.

^* This work was supported by a Grant-in-aid from National Institute of Biomedical Innovation, a Grant-in-aid from The Ministry of Public Health and Welfare, a Grant-in-aid from Japan Promotion of Science, and through Special Coordination Funds of the Ministry of Education, Culture, Sports, Science and Technology, the Japanese Government, Miyata Cardiology Research Promotion Funds, and the Ichiro Kanehara Foundation. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table S1 and Figs. S1-S3.

¹ To whom correspondence should be addressed: Dept. of Clinical Gene Therapy, Osaka University, Graduate School of Medicine, Suita 565-0871, Japan. Tel.: 81-6-6879-3406; Fax: 81-6-6879-3409; E-mail: morishit{at}cgt.med.osaka-u.ac.jp.

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