Investigating the role of TGFB signalling in preantral follicle development
File(s)
Author(s)
Oliver, Elizabeth Mary
Type
Thesis
Abstract
The neonatal ovary encompasses a finite pool of primordial follicles which serve the need of the entire reproductive lifespan. Follicle activation is therefore a tightly controlled process, the rate of which has a profound influence on fertility. Despite this the exact mechanisms responsible for maintaining the primordial follicle pool or, conversely, for activating the initiation of follicle recruitment remain unknown. Many of the extracellular signalling molecules implicated in early preantral follicle development are members of the transforming growth factor beta (TGFB) superfamily. The aim of this thesis was to examine the role of TGFB signalling in primordial follicle activation and subsequent early preantral follicle development. TGFB signalling is classically facilitated by the SMAD intracellular transcription factors. The SMAD2/3 cascade is the major TGFB signalling pathway expressed in the early preantral follicle. Pharmacological inhibition of the upstream receptors of the SMAD2/3 signalling cascade ALK4/5/7 with small molecule inhibitor SB505124 accelerated primordial follicle activation in a neonatal ovary culture while in a paradoxical manner inhibited development of the small multilayered preantral follicle in an isolated follicle culture. A screen of ligands that converge preferentially to the SMAD2/3 pathway highlighted TGFB2 as the most abundantly expressed in the early preantral follicle. TGFB2 inhibited primordial follicle activation in the neonatal ovary culture while in a differential manner promoted the growth of isolated small multilayered preantral follicles suggesting the action of TGFB2 is dependent on the developmental stage of the follicle. Pharmacological inhibition of ALK4/5/7 (SB505124) and the MAPK/ERK (U0126) signalling cascade ablated TGFB2 induced preantral follicle growth suggesting the coordinated action of SMAD and non-SMAD signalling underlies the context dependent action of TGFB2 in preantral follicle development. In conclusion these novel data suggest that TGFB signalling plays an important role in both maintenance of the primordial follicle pool and early stage preantral follicle development.
Version
Open Access
Date Issued
2016-12
Date Awarded
2017-05
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Hardy, Kate
Franks, Stephen
Sponsor
Medical Research Council (Great Britain)
Publisher Department
Department of Surgery & Cancer
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)