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J. Biol. Chem., Vol. 280, Issue 4, 2831-2839, January 28, 2005

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A Targeted Mutation of Nkd1 Impairs Mouse Spermatogenesis^*

Qin Li, Tomo-o Ishikawa, Hiroyuki Miyoshi, Masanobu Oshima, and Makoto M. Taketo¶

From the Department of Pharmacology, Graduate School of Medicine, Kyoto University, Yoshida-konoé-cho, Sakyo-ku, Kyoto 606-8501, Japan

Nkd1 is an antagonist of the canonical Wnt/-catenin signaling pathway. The EF-hand motif of Nkd1 is required for its inhibitory function. Early studies suggested that Nkd1 might play important roles in mouse embryonic development and tumorigenesis. We constructed Nkd1^-/- mice whose Nkd1 protein lacked the EF-hand and was unable to inhibit Wnt/-catenin signaling. The homozygotes were viable and grew normally, but their fertility in males was reduced. In wild-type adult testes, Nkd1 mRNA was expressed more abundantly in the elongating spermatids than in the round spermatids. Lack of EF-hand caused reductions in the testis weight and sperm count by 30 and 60%, respectively. During testis development, Nkd1 mRNA expression started at the 25th day after birth, coincident with the onset of Wnt1 expression. Nuclear localization of -catenin increased in the elongating spermatids, suggesting that the mutant Nkd1 failed to inhibit the Wnt/-catenin pathway. These results suggest that deletion of the EF-hand from Nkd1 reduces the number of the elongating spermatids at haploid stage. In contrast, the mutant Nkd1 did not affect intestinal polyposis in Apc⁷¹⁶ mice.

Received for publication, May 21, 2004 , and in revised form, November 15, 2004.

^* This work was supported in part by a grant-in-aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan and a grant from the Organization for Pharmaceutical Safety and Research. 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.

Supported by a fellowship from the Japan Society for the Promotion of Science.

Present address: Dept, of Pharmacology, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095.

^¶ To whom correspondence should be addressed. Tel.: 81-75-753-4391; Fax: 81-75-753-4402; E-mail: taketo{at}mfour.med.kyoto-u.ac.jp.

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