WNT4/beta-catenin pathway maintains female germ cell survival by inhibiting activin betaB in the mouse fetal ovary.
Female germ cells are essential for organogenesis of the ovary; without them, ovarian follicles do not form and functional and structural characteristics of the ovary are lost. We and others showed previously that when either Wnt4 or beta-catenin was inactivated in the fetal ovary, female germ cells underwent degeneration. In this study, we set out to understand whether these two factors belong to the same pathway and how they maintain female germ cell survival. We found that activation of beta-catenin in somatic cells in the Wnt4 knockout ovary restored germ cell numbers, placing beta-catenin downstream of WNT4. In the absence of Wnt4 or beta-catenin, female germ cells entered meiosis properly; however, they underwent apoptosis afterwards. Activin betaB (Inhbb), a subunit of activins, was upregulated in the Wnt4 and beta-catenin knockout ovaries, suggesting that Inhbb could be the cause for the loss of female germ cells, which are positive for activin receptors. Indeed, removal of Inhbb in the Wnt4 knockout ovaries prevented female germ cells from undergoing degeneration. We conclude that WNT4 maintains female germ cell survival by inhibiting Inhbb expression via beta-catenin in the somatic cells. Maintenance of female germ cells hinge upon a delicate balance between positive (WNT4 and beta-catenin) and negative (activin betaB) regulators derived from the somatic cells in the fetal ovary.
Liu
Chia-Feng
CF
Department of Veterinary Biosciences, University of Illinois, Urbana-Champaign, Illinois, United States of America.
Parker
Keith
K
Yao
Humphrey H-C
HH
D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D005260:Female; D005333:Fetus; D005854:Germ Cells / Q000166:cytology*; D028322:Inhibin-beta Subunits / Q000037:antagonists & inhibitors*; D008540:Meiosis; D051379:Mice; D010053:Ovary / Q000166:cytology* / Q000196:embryology; D051153:Wnt Proteins / Q000378:metabolism*; D060528:Wnt4 Protein; D051176:beta Catenin / Q000378:metabolism*
C498905:Inhbb protein, mouse; D051153:Wnt Proteins; D060528:Wnt4 Protein; C555582:Wnt4 protein, mouse; D051176:beta Catenin; D028322:Inhibin-beta Subunits
Mol Biol Rep. 2000 Sep;27(3):129-39
11254102
Genes Dev. 1994 Feb 15;8(4):414-27
8125256
Dev Biol. 2006 Oct 1;298(1):132-48
16930587
Mol Cell Endocrinol. 2003 Dec 15;211(1-2):1-7
14656469
Cancer Res. 2006 Feb 15;66(4):1964-73
16488995
Breast Cancer Res. 2003;5(2):63-8
12631383
Biol Reprod. 2006 May;74(5):978-83
16452457
Nature. 1999 Jul 8;400(6740):125-6
10408437
Development. 2008 Nov;135(22):3731-43
18927154
Hum Mol Genet. 2008 Oct 1;17(19):2949-55
18617533
Hum Mol Genet. 2009 Feb 1;18(3):405-17
18981061
Hum Mol Genet. 2008 May 1;17(9):1278-91
18250097
Science. 2002 Jun 21;296(5576):2181-3
12077403
Endocrinology. 1998 Feb;139(2):733-40
9449647
Dev Biol. 1999 Mar 15;207(2):470-5
10068477
Mol Cell Endocrinol. 2007 Feb;265-266:3-9
17208359
Toxicol Appl Pharmacol. 1999 Apr 15;156(2):81-95
10198273
Proc Natl Acad Sci U S A. 2006 Feb 21;103(8):2474-9
16461896
Reprod Nutr Dev. 1988;28(4B):1113-28
3244905
Histochem Cell Biol. 2001 Nov;116(5):427-39
11735006
Neoplasma. 2008;55(3):165-76
18348648
Science. 2006 Apr 28;312(5773):596-600
16574820
Exp Cell Res. 2004 Aug 15;298(2):369-87
15265686
Endocrinology. 2002 Nov;143(11):4358-65
12399432
Nature. 1999 Feb 4;397(6718):405-9
9989404
Dev Biol. 1997 Jul 1;187(1):107-13
9224678
Nature. 1990 May 10;345(6271):167-70
2336108
Am J Physiol Renal Physiol. 2002 Mar;282(3):F431-41
11832423
Dev Dyn. 2004 Jun;230(2):210-5
15162500
BMC Dev Biol. 2002 Jul 02;2:8
12095419
Nature. 1997 Sep 4;389(6646):73-7
9288969
Dev Biol. 2005 Sep 1;285(1):49-56
16139834
Semin Cell Dev Biol. 2005 Apr;16(2):245-59
15797835
Am J Physiol Renal Physiol. 2003 Apr;284(4):F653-62
12475749
Endocrinology. 2005 Sep;146(9):4016-23
15932923
Science. 1999 Dec 17;286(5448):2328-31
10600740
Proc Natl Acad Sci U S A. 1982 Nov;79(21):6584-8
6959138
J Exp Zool. 1990 Jan;253(1):61-70
2313242
Development. 2000 Nov;127(21):4645-54
11023867
Genes Dev. 1997 Dec 15;11(24):3286-305
9407023
Dev Biol. 2006 Dec 15;300(2):545-53
17055474
Dev Biol. 2005 Nov 15;287(2):361-77
16214126
Genesis. 2006 Sep;44(9):419-24
16937416
Mech Dev. 2008 May-Jun;125(5-6):498-507
18291628
Biol Reprod. 2009 Nov;81(5):842-9
19553598
Methods Mol Biol. 2004;262:87-107
14769957
Mol Hum Reprod. 2009 Apr;15(4):205-13
19218284
Cell Tissue Res. 2008 Dec;334(3):327-38
19002501
EMBO J. 1999 Nov 1;18(21):5931-42
10545105
Hum Mol Genet. 2008 May 1;17(9):1264-77
18250098
Endocrinology. 2000 Nov;141(11):4284-94
11089564
Nat Rev Mol Cell Biol. 2001 Nov;2(11):838-48
11715050
Front Neuroendocrinol. 1998 Oct;19(4):287-322
9799587
Endocr Rev. 2006 Jun;27(4):398-426
16543383
Development. 2007 Jul;134(13):2533-9
17537789