title: The exon 8-containing prosaposin gene splice variant is dispensable for mouse development, lysosomal function, and secretion.
abstract: 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.
authors.affiliation: Department of Cell Research and Immunology, Faculty of Life Sciences, Tel Aviv University, Ramat Aviv 69978, Israel.
authors.forename: Tsadok
authors.initials: T
authors.lastname: Cohen
authors.forename: Wojtek
authors.initials: W
authors.lastname: Auerbach
authors.forename: Liat
authors.initials: L
authors.lastname: Ravid
authors.forename: Jacques
authors.initials: J
authors.lastname: Bodennec
authors.forename: Amos
authors.initials: A
authors.lastname: Fein
authors.forename: Anthony H
authors.initials: AH
authors.lastname: Futerman
authors.forename: Alexandra L
authors.initials: AL
authors.lastname: Joyner
authors.forename: Mia
authors.initials: M
authors.lastname: Horowitz
mesh_terms: D017398:Alternative Splicing / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001216:Asparagine / Q000235:genetics; D004622:Embryo, Mammalian / Q000166:cytology; D005091:Exons / Q000235:genetics*; D005298:Fertility / Q000235:genetics / Q000502:physiology; D005973:Glutamine / Q000235:genetics; D050356:Lipid Metabolism; D008055:Lipids / Q000032:analysis; D008247:Lysosomes / Q000502:physiology; D008297:Male; D051379:Mice / Q000235:genetics / Q000254:growth & development*; D008817:Mice, Mutant Strains; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D049231:Saposins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D017384:Sequence Deletion; D013234:Stem Cells / Q000378:metabolism; D013737:Testis / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D008055:Lipids; D020033:Protein Isoforms; C483344:Psap protein, mouse; D012333:RNA, Messenger; D049231:Saposins; D005973:Glutamine; D001216:Asparagine
references.citation: Glia. 1999 Jun;26(4):353-60
references.pmid: 10383054
references.citation: Neurosci Lett. 1999 May 21;267(1):73-6
references.pmid: 10400252
references.citation: J Biol Chem. 1957 May;226(1):497-509
references.pmid: 13428781
references.citation: Biochemistry. 1963 Nov-Dec;2:1259-63
references.pmid: 14093899
references.citation: J Lipid Res. 2000 Sep;41(9):1524-31
references.pmid: 10974060
references.citation: J Androl. 2000 Nov-Dec;21(6):765-75
references.pmid: 11105903
references.citation: Hum Mol Genet. 2001 Apr 15;10(9):927-40
references.pmid: 11309366
references.citation: J Androl. 2001 May-Jun;22(3):361-75
references.pmid: 11330636
references.citation: Muscle Nerve. 2001 Jun;24(6):799-808
references.pmid: 11360264
references.citation: Hum Mol Genet. 2001 May 15;10(11):1191-9
references.pmid: 11371512
references.citation: J Cereb Blood Flow Metab. 2001 Nov;21(11):1295-302
references.pmid: 11702044
references.citation: Proc Natl Acad Sci U S A. 2003 Jan 7;100(1):38-43
references.pmid: 12518053
references.citation: Asian J Androl. 2003 Mar;5(1):57-63
references.pmid: 12647005
references.citation: Philos Trans R Soc Lond B Biol Sci. 2003 May 29;358(1433):847-61
references.pmid: 12803917
references.citation: J Lipid Res. 2003 Jul;44(7):1413-9
references.pmid: 12730305
references.citation: Cell Biol Int. 2003;27(8):675-87
references.pmid: 12867159
references.citation: J Neurotrauma. 2003 Aug;20(8):755-65
references.pmid: 12965054
references.citation: Prog Neurobiol. 2003 Aug;70(5):387-407
references.pmid: 14511698
references.citation: Mol Cell Biol. 2003 Dec;23(24):9245-50
references.pmid: 14645534
references.citation: Cell Mol Life Sci. 2004 Mar;61(6):657-68
references.pmid: 15052409
references.citation: J Neuropathol Exp Neurol. 2004 Jul;63(7):721-34
references.pmid: 15290897
references.citation: Brain Res Mol Brain Res. 2004 Oct 22;129(1-2):8-19
references.pmid: 15469878
references.citation: Hum Mol Genet. 2004 Nov 1;13(21):2709-23
references.pmid: 15345707
references.citation: Mech Dev. 2000 Feb;90(2):155-65
references.pmid: 10640701
references.citation: J Inherit Metab Dis. 2000 Feb;23(1):63-76
references.pmid: 10682309
references.citation: Anal Biochem. 1976 May 7;72:248-54
references.pmid: 942051
references.citation: Biochim Biophys Acta. 1977 Apr 12;481(2):561-72
references.pmid: 15613
references.citation: Nature. 1977 Dec 22-29;270(5639):725-7
references.pmid: 563524
references.citation: J Biochem. 1989 Feb;105(2):152-4
references.pmid: 2498298
references.citation: Eur J Pediatr. 1989 Oct;149(1):31-9
references.pmid: 2514102
references.citation: Biochem Biophys Res Commun. 1989 Dec 29;165(3):1191-7
references.pmid: 2610686
references.citation: Biochem Biophys Res Commun. 1990 Jan 30;166(2):1017-23
references.pmid: 2302219
references.citation: Biol Reprod. 1989 Nov;41(5):941-8
references.pmid: 2624858
references.citation: Proc Natl Acad Sci U S A. 1990 Apr;87(7):2541-4
references.pmid: 2320574
references.citation: J Biol Chem. 1991 Apr 25;266(12):7556-60
references.pmid: 2019586
references.citation: Biochem Biophys Res Commun. 1991 Apr 30;176(2):668-74
references.pmid: 2025281
references.citation: FEBS Lett. 1991 Jun 17;284(1):57-9
references.pmid: 2060627
references.citation: Hum Genet. 1991 Jun;87(2):211-5
references.pmid: 2066109
references.citation: Eur J Pediatr. 1991 Jun;150(8):584-91
references.pmid: 1683286
references.citation: Biochem Biophys Res Commun. 1991 Nov 27;181(1):286-92
references.pmid: 1958198
references.citation: J Biol Chem. 1992 Feb 15;267(5):3312-5
references.pmid: 1371116
references.citation: J Lipid Res. 1992 Sep;33(9):1255-67
references.pmid: 1402395
references.citation: Proc Natl Acad Sci U S A. 1992 Dec 1;89(23):11254-8
references.pmid: 1454804
references.citation: Somat Cell Mol Genet. 1993 Jan;19(1):1-7
references.pmid: 8460394
references.citation: Arch Biochem Biophys. 1993 Jul;304(1):110-6
references.pmid: 8323276
references.citation: Cell Mol Biol (Noisy-le-grand). 1993 May;39(3):287-99
references.pmid: 8334382
references.citation: Biochem Biophys Res Commun. 1994 May 16;200(3):1440-8
references.pmid: 8185598
references.citation: J Biol Chem. 1994 Aug 12;269(32):20528-32
references.pmid: 8051151
references.citation: Proc Natl Acad Sci U S A. 1994 Sep 27;91(20):9593-6
references.pmid: 7937812
references.citation: Biochem Biophys Res Commun. 1994 Oct 28;204(2):994-1000
references.pmid: 7980569
references.citation: J Mol Neurosci. 1994 Spring;5(1):59-67
references.pmid: 7857780
references.citation: Science. 1995 Aug 4;269(5224):679-82
references.pmid: 7624797
references.citation: J Biol Chem. 1996 Apr 5;271(14):8416-23
references.pmid: 8626540
references.citation: J Biol Chem. 1996 Jul 19;271(29):17312-20
references.pmid: 8663398
references.citation: Hum Mol Genet. 1996 Jun;5(6):711-25
references.pmid: 8776585
references.citation: J Neurochem. 1996 May;66(5):2019-25
references.pmid: 8780031
references.citation: Proc Natl Acad Sci U S A. 1997 Apr 29;94(9):4778-81
references.pmid: 9114068
references.citation: Mol Reprod Dev. 1997 Sep;48(1):1-8
references.pmid: 9266755
references.citation: Int J Androl. 1997 Jun;20(3):171-9
references.pmid: 9354187
references.citation: Nat Genet. 1997 Dec;17(4):404-10
references.pmid: 9398841
references.citation: J Androl. 1998 Mar-Apr;19(2):156-64
references.pmid: 9570738
references.citation: Brain Res Dev Brain Res. 1998 Oct 1;110(2):249-55
references.pmid: 9748612
references.citation: J Neurochem. 1998 Dec;71(6):2313-21
references.pmid: 9832129
references.citation: Biochem J. 1999 Feb 1;337 ( Pt 3):433-43
references.pmid: 9895286
references.citation: J Androl. 1999 Jan-Feb;20(1):34-41
references.pmid: 10100471
references.citation: Eur J Hum Genet. 1999 Feb-Mar;7(2):125-30
references.pmid: 10196694