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J. Biol. Chem., Vol. 282, Issue 33, 24065-24074, August 17, 2007

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HOP/NECC1, A Novel Regulator of Mouse Trophoblast Differentiation^*

Kazuo Asanoma¹, Hidenori Kato, Shinichiro Yamaguchi, Chong Hyun Shin^¶, Zhi-Ping Liu^||, Kiyoko Kato, Takafumi Inoue^**, Yoko Miyanari, Koji Yoshikawa, Kenzo Sonoda^**, Kotaro Fukushima^**, and Norio Wake^**

From the Division of Molecular and Cell Therapeutics, Department of Molecular Genetics and the Department of Pathology, Medical Institute of Bioregulation, Kyushu University and the ^**Department of Obstetrics and Gynecology, Kyushu University Faculty of Medicine, 3-1-1 Maidashi, Higashi-ku, Fukuoka City, Fukuoka 812-8582, Japan, the Department of Gynecology, Hokkaido Cancer Center, 4-2-3-54 Kikusui, Shiraishi-ku, Sapporo City, Hokkaido, 003-0000, Japan, the ^¶Department of Biochemistry and Biophysics, University of California, San Francisco, California 94143, and the ^||Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390

Homeodomain-only protein/not expressed in choriocarcinoma clone 1 (HOP/NECC1) is a newly identified gene that modifies the expression of cardiac-specific genes and thereby regulates heart development. More recently, HOP/NECC1 was reported to be a suppressor of choriocarcinogenesis. Here, we examined the temporal expression profile of HOP/NECC1 in wild-type mouse placenta. We found that E8.5–E9.5 wild-type placenta expressed HOP/NECC1 in the giant cell and spongiotrophoblast layers. HOP/NECC1 (-/-) placenta exhibited marked propagation of giant cell layers and, in turn reduction of spongiotrophoblast formation. We demonstrated SRF transcriptional activity increased in the differentiating trophoblasts and forced expression of SRF in a trophoblast stem (TS) cell line induces the differentiation into giant cells. Negative regulation of SRF (serum response factor) by the binding of HOP/NECC1 protein contributed at least in part to the generation of these placental defects. Gradual induction of HOP/NECC1 in response to differentiation stimuli may result in the decision to differentiate into a particular type of trophoblastic cell lineage and result in non-lethal defects shown by the HOP/NECC1 (-/-) placentas.

Received for publication, February 16, 2007 , and in revised form, June 15, 2007.

^* This work was supported in part by Kanzawa Medical Research Foundation and Grants-in-Aid 17791124 and 19791154 from the Ministry of Education, Culture, Sports, Science and Technology, Japan. 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.

¹ To whom correspondence should be addressed. E-mail: asanoma{at}med.kyushu-u.ac.jp.

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