Mice deficient in the serine/threonine protein kinase VRK1 are infertile due to a progressive loss of spermatogonia.
The VRK1 protein kinase has been implicated as a pro-proliferative factor. Genetic analyses of mutant alleles of the Drosophila and Caenorhabditis elegans VRK1 homologs have revealed phenotypes ranging from embryonic lethality to mitotic and meiotic defects with resultant sterility. Herein, we describe the first genetic analysis of murine VRK1. Two lines of mice containing distinct gene-trap integrations into the Vrk1 locus were established. Insertion into intron 12 (GT12) spared VRK1 function, enabling the examination of VRK1 expression in situ. Insertion into intron 3 (GT3) disrupted VRK1 function, but incomplete splicing to the gene trap rendered this allele hypomorphic (approximately 15% of wild-type levels of VRK1 remain). GT3/GT3 mice are viable, but both males and females are infertile. In testes, VRK1 is expressed in Sertoli cells and spermatogonia. The infertility of GT3/GT3 male mice results from a progressive defect in spermatogonial proliferation or differentiation, culminating in the absence of mitotic and meiotic cells in adult testis. These data demonstrate an important role for VRK1 in cell proliferation and confirm that the need for VRK1 during gametogenesis is evolutionarily conserved.
Wiebe
Matthew S
MS
Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
Nichols
R Jeremy
RJ
Molitor
Tyler P
TP
Lindgren
Jill K
JK
Traktman
Paula
P
D000483:Alleles; D000818:Animals; D034961:Antigens, Nuclear / Q000378:metabolism; D049109:Cell Proliferation; D005260:Female; D007247:Infertility, Female / Q000378:metabolism; D007248:Infertility, Male / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D008297:Male; D008540:Meiosis; D051379:Mice; D008810:Mice, Inbred C57BL; D008938:Mitosis; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012708:Sertoli Cells / Q000378:metabolism*; D013093:Spermatogonia / Q000378:metabolism*
D034961:Antigens, Nuclear; D051741:Kruppel-Like Transcription Factors; D018809:Proliferating Cell Nuclear Antigen; D000075722:Promyelocytic Leukemia Zinc Finger Protein; C513267:Zbtb16 protein, mouse; D017346:Protein Serine-Threonine Kinases; C484518:Vrk1 protein, mouse
Nature. 2005 Aug 18;436(7053):1030-4
16107850
Nat Cell Biol. 2006 Aug;8(8):863-9
16845380
J Biol Chem. 2004 Jun 25;279(26):27458-65
15105425
Biol Reprod. 2003 Dec;69(6):1815-21
12890724
Arch Biochem Biophys. 2007 Sep 1;465(1):219-26
17617371
Mol Cell Biol. 2009 Mar;29(5):1189-201
19103756
Mol Cell Biol. 2004 Dec;24(23):10366-80
15542844
Development. 2000 May;127(10):2125-31
10769236
FEBS Lett. 2003 Jun 5;544(1-3):176-80
12782311
J Biol Chem. 2004 Feb 27;279(9):7934-46
14645249
Dev Biol. 2006 Jun 1;294(1):161-7
16564520
Mol Cell Proteomics. 2008 Nov;7(11):2199-214
18617507
Nat Genet. 2004 Jun;36(6):653-9
15156143
Mol Biol Cell. 2006 May;17(5):2451-64
16495336
Development. 1991 Oct;113(2):689-99
1723681
J Cell Sci. 2008 Sep 15;121(Pt 18):3035-41
18713830
Dev Dyn. 1998 Jun;212(2):171-80
9626493
Development. 1998 Nov;125(22):4585-93
9778516
Endocrinology. 1999 Dec;140(12):5894-900
10579355
Curr Biol. 2002 Nov 19;12(22):1959-64
12445391
J Cell Biol. 2007 Dec 3;179(5):817-24
18039935
Genes Dev. 2004 Apr 15;18(8):877-88
15078818
Stem Cells. 2008 Jun;26(6):1587-97
18339773
Annu Rev Cell Dev Biol. 2008;24:263-86
18588486
Mol Cell Biol. 2002 May;22(10):3450-9
11971976
J Cell Biol. 2005 Nov 21;171(4):593-602
16301329
Oncogene. 2004 Nov 25;23(55):8950-8
15378002
EMBO J. 2005 May 18;24(10):1810-20
15889149
Nat Genet. 2004 Jun;36(6):647-52
15156142
Biochim Biophys Acta. 2008 Jan;1783(1):49-58
18035061
Lung Cancer. 2007 Dec;58(3):303-9
17689819
EMBO J. 2002 Jul 15;21(14):3728-38
12110585
Dev Biol. 1994 Jun;163(2):331-40
8200475
Genomics. 1997 Oct 15;45(2):327-31
9344656
Mol Cancer Res. 2006 Mar;4(3):177-85
16547155
Arch Biochem Biophys. 2002 Mar 1;399(1):1-5
11883897
Oncogene. 2000 Jul 27;19(32):3656-64
10951572
PLoS One. 2008 Aug 20;3(8):e2994
18714348
Genes Dev. 2004 Mar 1;18(5):512-27
15014043
Genes Dev. 2005 Nov 1;19(21):2571-82
16230526
Biol Reprod. 2003 Jul;69(1):161-8
12606378
EMBO J. 2007 Jan 10;26(1):132-43
17170708
Mol Cell Biol. 2007 Dec;27(24):8533-46
17938195
Oncogene. 2004 May 6;23(21):3822-9
15021912
Histol Histopathol. 2009 Jun;24(6):749-59
19337973
Arch Biochem Biophys. 1998 Apr 1;352(1):31-6
9521809