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J. Biol. Chem., Vol. 278, Issue 48, 48377-48385, November 28, 2003

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Inactivation of a Testis-specific Lis1 Transcript in Mice Prevents Spermatid Differentiation and Causes Male Infertility^*

Karim Nayernia, Franz Vauti, Andreas Meinhardt¶, Christina Cadenas, Stephan Schweyer||, Barbara I. Meyer**, Iris Schwandt, Kamal Chowdhury**, Wolfgang Engel, and Hans-Henning Arnold

From the Institute for Human Genetics and ^||Department of Pathology, University of Göttingen, Göttingen 37073, the Department of Cell and Molecular Biology, Technical University Braunschweig, Spielmannstrasse7, Braunschweig 38106, the ^¶Department of Anatomy and Cell Biology, University of Giessen, Giessen 35378, and the ^**Max-Planck-Institute for Biophysical Chemistry, Göttingen 37077, Germany

Lis1 protein is the non-catalytic component of platelet-activating factor acetylhydrolase 1b (PAF-AH 1B) and associated with microtubular structures. Hemizygous mutations of the LIS1 gene cause type I lissencephaly, a brain abnormality with developmental defects of neuronal migration. Lis1 is also expressed in testis, but its function there has not been determined. We have generated a mouse mutant (LIS1^GT/GT) by gene trap integration leading to selective disruption of a Lis1 splicing variant in testis. Homozygous mutant males are infertile with no other apparent phenotype. We demonstrate that Lis1 is predominantly expressed in spermatids, and spermiogenesis is blocked when Lis1 is absent. Mutant spermatids fail to form correct acrosomes and nuclei appear distorted in size and shape. The tissue architecture in mutant testis appears severely disturbed displaying collapsed seminiferous tubules, mislocated germ cells, and increased apoptosis. These results provide evidence for an essential and hitherto uncharacterized role of the Lis1 protein in spermatogenesis, particularly in the differentiation of spermatids into spermatozoa.

Received for publication, August 28, 2003 , and in revised form, September 15, 2003.

^* This work was supported by grants of the Deutsche Forschungsgemeinschaft and the Fond der Chemischen Industrie. 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.

To whom correspondence should be addressed. Tel.: 49-531-391-5735; Fax: 49-531-391-8178; E-mail: h.arnold{at}tu-bs.de.

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