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Science 23 May 2003:
Vol. 300. no. 5623, pp. 1291 - 1295
DOI: 10.1126/science.1083022
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Reports

Essential Role of Fkbp6 in Male Fertility and Homologous Chromosome Pairing in Meiosis

Michael A. Crackower,1*{dagger} Nadine K. Kolas,2* Junko Noguchi,4 Renu Sarao,1 Kazuhiro Kikuchi,4 Hiroyuki Kaneko,4 Eiji Kobayashi,5 Yasuhiro Kawai,6 Ivona Kozieradzki,1 Rushin Landers,1 Rong Mo,7 Chi-Chung Hui,7 Edward Nieves,3 Paula E. Cohen,2 Lucy R. Osborne,8 Teiji Wada,1 Tetsuo Kunieda,6 Peter B. Moens,9 Josef M. Penninger1{ddagger}

Meiosis is a critical stage of gametogenesis in which alignment and synapsis of chromosomal pairs occur, allowing for the recombination of maternal and paternal genomes. Here we show that FK506 binding protein (Fkbp6) localizes to meiotic chromosome cores and regions of homologous chromosome synapsis. Targeted inactivation of Fkbp6 in mice results in aspermic males and the absence of normal pachytene spermatocytes. Moreover, we identified the deletion of Fkbp6 exon 8 as the causative mutation in spontaneously male sterile as/as mutant rats. Loss of Fkbp6 results in abnormal pairing and misalignments between homologous chromosomes, nonhomologous partner switches, and autosynapsis of X chromosome cores in meiotic spermatocytes. Fertility and meiosis are normal in Fkbp6 mutant females. Thus, Fkbp6 is a component of the synaptonemal complex essential for sex-specific fertility and for the fidelity of homologous chromosome pairing in meiosis.

1 Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), c/o Dr. Bohrgasse 7, 1030, Vienna, Austria
2 Department of Molecular Genetics, Laboratory for Macromolecular Analysis and Proteomics, Albert Einstein College of Medicine (AECOM), 1300 Morris Park Avenue, Bronx, NY 10461, USA.
3 Department of Biochemistry, Laboratory for Macromolecular Analysis and Proteomics, Albert Einstein College of Medicine (AECOM), 1300 Morris Park Avenue, Bronx, NY 10461, USA.
4 Germ Cell Conservation Laboratory, National Institute of Agrobiological Sciences, Kannondai, Tsukuba, Ibaraki 305-8602, Japan
5 National Livestock Breeding Center, Odakura, Nishigo, Fukushima 961-851, Japan
6 Graduate School of Natural Science and Technology, Okayama University, Okayama 700-0082 Japan
7 Program in Developmental Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
8 Departments of Medicine and Molecular and Medical Genetics, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada
9 Department of Biology, York University, Toronto, ON M3J 1P3, Canada



{dagger} Present address: Department of Protein Sciences, Amgen, Thousand Oaks, CA 91320, USA.

* These authors contributed equally to this work.

{ddagger} To whom correspondence should be addressed. E-mail: josef.penninger{at}oeaw.ac.at

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