The role of the neurotrophin receptor TrkB in regulating oocyte survival in the developing mammalian ovary.

Lead Research Organisation: University of Edinburgh
Department Name: Centre of Population Health Sciences

Abstract

At or shortly after birth, the mammalian ovary contains the lifetime?s supply of oocytes, enclosed within ovarian follicles. The follicles form from a pool of germ cells termed oogonia. During follicle formation, there is a massive wave of germ cell death. Indeed, only around 10% of oognia survive to form follicles in both mice and humans. The regulation of this germ cell death is not understood, although the process is one of the main factors determining the reproductive lifespan of female mammals.

We have recently obtained results showing that a neurotrophin receptor, TrkB, is involved in this process (Spears et al., 2003). TrkB is a member of a membrane-bound receptor family first discovered in the nervous system. The Trk receptor?s primary role in the nervous system is in the regulation of cell survival: neurons containing one or more of the Trk receptors might require the presence of sufficient concentration of the appropriate ligands (the neurotrophins) to bind to and activate the receptors. We hypothesise that the TrkB receptor and its ligands play a similar role during ovarian follicle formation, and that this is a specific requirement of the germ cells during the period that follicles form. We propose a series of in vivo and culture experiments to investigate our hypothesis.

Technical Summary

As the mammalian ovary forms, it produces an excess of germ cells (termed oogonia), only a small percentage of which will develop into oocytes and form ovarian follicles. The mechanism by which germ cell survival or death is regulated is poorly understood, although the process is crucial for determination of the female reproductive lifespan.

We have evidence, from transgenic mice and from various in vitro experiments, showing that the neurotrophin receptor TrkB (a glycoprotein tyrosine receptor kinase) and its ligands are involved in this process: trkB-/- knockout mice have reduced numbers of ovarian follicles and wild type mouse ovaries cultured in the presence of a blocker of Trk receptor function exhibit widespread germ cell death (Spears et al, 2003).

Our aims here are:
(i) to test our hypothesis that it is the germ cell that requires TrkB signalling, and that it is required as a survival factor only by primordial follicles.
(ii) to investigate the function of the truncated forms of the receptor which lack the tyrosine kinase domain (this form being the most prevalent one in the ovary), and
(iii) to determine what ligand(s) are involved in this process.

We plan to use a mixture of in vivo and in vitro techniques to achieve our aims, investigating ovarian development in trkB-/- mice and culturing ovaries with blockers of the Trk receptors and their ligands.

Publications

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Childs AJ (2010) Differential expression and regulation by activin of the neurotrophins BDNF and NT4 during human and mouse ovarian development. in Developmental dynamics : an official publication of the American Association of Anatomists

 
Description Public talk 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Public talk as part of series of talks to engage public audience in scientific research.

Talks are very successful.
Year(s) Of Engagement Activity 2007,2008