The role of neurotrophin receptors in female germ-cell survival in mouse and human

被引:89
作者
Spears, N
Molinek, MD
Robinson, LLL
Fulton, N
Cameron, H
Shimoda, K
Telfer, EE
Anderson, RA
Price, DJ
机构
[1] Univ Edinburgh, Edinburgh EH8 9XD, Midlothian, Scotland
[2] Univ Edinburgh, Ctr Reprod Biol, MRC, Human Reprod Sci Unit, Edinburgh EH16 4SA, Midlothian, Scotland
[3] Univ Edinburgh, Inst Cellular & Mol Biol, Edinburgh, Midlothian, Scotland
来源
DEVELOPMENT | 2003年 / 130卷 / 22期
基金
英国惠康基金;
关键词
Trk; oogonia; oocyte; survival; human; mouse; neurotrophin;
D O I
10.1242/dev.00707
中图分类号
Q [生物科学];
学科分类号
07 ; 0710 ; 09 ;
摘要
During mammalian ovary formation, the production of ovarian follicles is accompanied by an enormous loss of germ cells. It is not known how this loss is regulated. We have investigated the role of the Trk tyrosine kinase receptors, primarily TrkB, in this process. The ovaries of TrkB(-/-) and TrkC(-/-) mice with a mixed (129Sv x C57BL/6) genetic background were examined shortly after birth. Around 50% of TrkB(-/-) mice had grossly abnormal ovaries that contained greatly reduced numbers of follicles. No defects were found in the ovaries of TrkC(-/-) mice. Congenic TrkB(-/-) mice were generated on 129Sv and C57BL/6 backgrounds: whereas the former had a mixed ovarian phenotype similar to that of the original colony of mice, the ovaries of all offspring of the C57BL/6 congenic line contained reduced numbers of follicles. RT-PCR showed that mRNA encoding TrkB and its two ligands, neurotrophin 4 (NT4) and brain-derived neurotrophic factor (BDNF), were present throughout the period of follicle formation in the mouse. In situ hybridisation showed that TrkB was expressed primarily in the germ cells before and after follicle formation. Mouse neonatal and fetal ovaries and human fetal ovaries were cultured in the presence of K252a, a potent inhibitor of all Trk receptors. In mice, K252a inhibited the survival of germ cells in newly formed (primordial) follicles. This effect was rescued by the addition of basic fibroblast growth factor (bFGF) to the culture medium. Combined addition of both BDNF and NT4 blocking antibodies lowered germ-cell survival, indicating that these TrkB ligands are required in this process. The results indicate that signalling through TrkB is an important component of the mechanism that regulates the early survival of female germ cells.
引用
收藏
页码:5481 / 5491
页数:11
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