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Genes to Cells (2006) 11, 1405-1417. doi:10.1111/j.1365-2443.2006.01028.x
© 2006 Blackwell Publishing or its licensors

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Female infertility in mice deficient in midkine and pleiotrophin, which form a distinct family of growth factors

Hisako Muramatsu1,2, Peng Zou1, Nobuyuki Kurosawa1, Keiko Ichihara-Tanaka1,3, Kiyoko Maruyama1, Kazuhiko Inoh1, Takayuki Sakai1, Lan Chen1, Masahiro Sato4 and Takashi Muramatsu1,3,*

1 Department of Biochemistry and
2 Division of Disease Models, Center for Neurological Disease and Cancer, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
3 Department of Health Science, Faculty of Psychological and Physical Sciences, Aichi Gakuin University, 12 Araike, Iwasaki-cho, Nisshin, Aichi 470-0195, Japan
4 Division of Basic Molecular Science and Molecular Medicine, School of Medicine, Tokai University, Bohseidai, Isehara, Kanagawa 259-1193, Japan

Midkine and pleiotrophin form a family of growth factors. Mice deficient in one of the genes show few abnormalities on reproduction and development. To understand their roles in these processes, we produced mice deficient in both genes; the double deficient mice were born in only one third the number expected by Mendelian segregation and 4 weeks after birth weighed about half as much as wild-type mice. Most of the female double deficient mice were infertile. In these mice, the numbers of mature follicles and of ova at ovulation were reduced compared to numbers in wild-type mice. Both midkine and pleiotrophin were expressed in the follicular epithelium and granulosa cells of the ovary. The expression of these factors in the uterus was dramatically altered during the estrous cycle. The diestrus and proestrus periods were long and the estrus period was short in the double deficient mice, indicating the role of the factors in the estrous cycle. Furthermore, vaginal abnormality was found in about half of the double deficient mice. These abnormalities in combination resulted in female infertility. Therefore, midkine and pleiotrophin, together with their signaling receptors, play important roles in the female reproductive system.


Communicated by: Shinichi Aizawa

* Correspondence: E-mail: tmurama{at}dpc.aichi-gakuin.ac.jp







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