Association of Meiotic Arrest with Lack of BOULE Protein Expression in Infertile Men
C. Marc Luetjens,
Eugene Y. Xu,
Renee A. Rejo Pera,
Axel Kamischke,
Eberhard Nieschlag and
Jörg Gromoll
Institute of Reproductive Medicine (C.M.L., A.K., E.N., J.G.), Westphalian Wilhelms-University, D-48129 Muenster, Germany; and Departments of Obstetrics, Gynecology, and Reproductive Sciences, Physiology, and Urology (E.Y.X., R.A.R.P.), Program in Development and Stem Cell Biology, University of California, San Francisco, California 94143-0556
Address all correspondence and requests for reprints to: Prof. Dr. J. Gromoll, Institute for Reproductive Medicine, Domagkstrasse 11, D-48149 Münster, Germany. E-mail: gromolj{at}uni-muenster.de.
Spermatogenesis is a complex developmental process of mitoticand meiotic cell divisions that ultimately results in productionof haploid spermatozoa. Recent studies in flies demonstratethat the BOULE gene encodes a key factor of meiosis in malegerm cells, regulating the expression of twine, a cdc25 phosphatase,which promotes progression through meiosis. In this study, weinvestigated whether a common mechanism underlies the blockof germ cell maturation observed in idiopathic and nonidiopathicazoospermic patients with meiotic arrest. We examined, by immunohistochemistry,BOULE and CDC25A phosphatase protein, the human homolog of twine,expression in 47 men with meiotic arrest, mixed atrophy, ornormal spermatogenesis. The presence of genetic alterationswithin the BOULE gene was investigated by single-stranded conformationpolymorphism. BOULE protein expression in men with completespermatogenesis can be restricted to stages from leptotene upto stages of late spermatocytes, whereas CDC25A expression rangesfrom leptotene spermatocytes to elongating spermatids. Althoughspermatocytes were present in all testicular biopsies with meioticarrest (28 testes), BOULE protein expression was completelylacking. In addition, in nearly all biopsies in which BOULEwas absent, CDC25A was concomitantly lacking. However, no mutationsor polymorphisms in the BOULE gene were identified, which couldexplain the lack of BOULE or CDC25A expression. These resultsindicate that a major group of infertile men with meiotic arrestlack BOULE protein and its putative target, CDC25A expression.The spermatogenic failure seems to arise from factor(s) upstreamof BOULE, which are possibly involved in regulating transcriptionand/or translation of BOULE. Thus, the spermatogenic damageleading to meiotic arrest is independent of the etiology andindicates that BOULE is a possible fundamental mediator of meiotictransition in the human.
This work was supported by the Fritz-Thyssen and Alexander vonHumboldt Foundations and by a grant of the Innovative MedicalResearch of the University (IMF-GR110311).
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