PMID- 14507777 OWN - NLM STAT- MEDLINE DCOM- 20040107 LR - 20181113 IS - 0950-1991 (Print) IS - 1477-9129 (Electronic) IS - 0950-1991 (Linking) VI - 130 IP - 22 DP - 2003 Nov TI - The role of neurotrophin receptors in female germ-cell survival in mouse and human. PG - 5481-91 AB - 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. FAU - Spears, Norah AU - Spears N AD - Biomedical Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK. norah.spears@ed.ac.uk FAU - Molinek, Michael D AU - Molinek MD FAU - Robinson, Lynne L L AU - Robinson LL FAU - Fulton, Norma AU - Fulton N FAU - Cameron, Helen AU - Cameron H FAU - Shimoda, Kohji AU - Shimoda K FAU - Telfer, Evelyn E AU - Telfer EE FAU - Anderson, Richard A AU - Anderson RA FAU - Price, David J AU - Price DJ LA - eng GR - Wellcome Trust/United Kingdom GR - 065620/Wellcome Trust/United Kingdom PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20030924 PL - England TA - Development JT - Development (Cambridge, England) JID - 8701744 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Carbazoles) RN - 0 (Enzyme Inhibitors) RN - 0 (Indole Alkaloids) RN - 0 (Nerve Growth Factors) RN - 97161-97-2 (staurosporine aglycone) RN - EC 2.7.10.1 (Receptor, trkB) RN - EC 2.7.10.1 (Receptor, trkC) RN - P658DCA9XD (neurotrophin 4) SB - IM MH - Animals MH - Brain-Derived Neurotrophic Factor/biosynthesis/genetics MH - Carbazoles/pharmacology MH - Cell Survival/physiology MH - Enzyme Inhibitors/pharmacology MH - Female MH - Humans MH - Indole Alkaloids MH - Mice MH - Mice, Transgenic MH - Nerve Growth Factors/biosynthesis/genetics MH - Ovary/drug effects MH - Ovum/*metabolism MH - Receptor, trkB/*genetics/metabolism MH - Receptor, trkC/*genetics/metabolism PMC - PMC6209142 MID - EMS80189 EDAT- 2003/09/26 05:00 MHDA- 2004/01/08 05:00 PMCR- 2018/10/31 CRDT- 2003/09/26 05:00 PHST- 2003/09/26 05:00 [pubmed] PHST- 2004/01/08 05:00 [medline] PHST- 2003/09/26 05:00 [entrez] PHST- 2018/10/31 00:00 [pmc-release] AID - dev.00707 [pii] AID - 10.1242/dev.00707 [doi] PST - ppublish SO - Development. 2003 Nov;130(22):5481-91. doi: 10.1242/dev.00707. Epub 2003 Sep 24.