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Molecular and Cellular Biology, March 2005, p. 2431-2440, Vol. 25, No. 6
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.6.2431-2440.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

The Exon 8-Containing Prosaposin Gene Splice Variant Is Dispensable for Mouse Development, Lysosomal Function, and Secretion

Tsadok Cohen,¹ Wojtek Auerbach,² Liat Ravid,¹ Jacques Bodennec,³ Amos Fein,⁴ Anthony H. Futerman,³ Alexandra L. Joyner,² and Mia Horowitz^1*

Department of Cell Research and Immunology, Faculty of Life Sciences,¹ Department of Cell and Developmental Biology, Sackler School of Medicine, Tel Aviv University, Ramat Aviv,⁴ Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel,³ Developmental Genetics, Skirball Institute, NYU Medical Center, New York, New York²

Received 12 September 2004/ Returned for modification 20 November 2004/ Accepted 15 December 2004

Prosaposin is a multifunctional protein with diverse functions. Intracellularly, prosaposin is a precursor of four sphingolipid activator proteins, saposins A to D, which are required for hydrolysis of sphingolipids by several lysosomal exohydrolases. Secreted prosaposin has been implicated as a neurotrophic, myelinotrophic, and myotrophic factor as well as a spermatogenic factor. It has also been implicated in fertilization. The human and the mouse prosaposin gene has a 9-bp exon (exon 8) that is alternatively spliced, resulting in an isoform with three extra amino acids, Gln-Asp-Gln, within the saposin B domain. Alternative splicing in the prosaposin gene is conserved from fish to humans, tissue specific, and regulated in the brain during development and nerve regeneration-degeneration processes. To elucidate the physiological role of alternative splicing, we have generated a mouse lacking exon 8 by homologous recombination. The exon 8 prosaposin mutant mice are healthy and fertile with no obvious phenotype. No changes were detected in prosaposin secretion or in accumulation and metabolism of gangliosides, sulfatides, neutral glycosphingolipids, neutral phospholipids, other neutral lipids, and ceramide. These data strongly indicate that the prosaposin variant containing the exon 8-encoded three amino acids is dispensable for normal mouse development and fertility as well as for prosaposin secretion and its lysosomal function, at least in the presence of the prosaposin variant missing the exon 8-encoded three amino acids.

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* Corresponding author. Mailing address: Department of Cell Research and Immunology, Tel Aviv University, Ramat Aviv 69978, Israel. Phone: 972-3-6409285. Fax: 972-3-6422046. E-mail: horwitzm{at}post.tau.ac.il.

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Molecular and Cellular Biology, March 2005, p. 2431-2440, Vol. 25, No. 6
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.6.2431-2440.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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