Abstract
Glial cell line-derived neurotrophic factor (GDNF) is expressed at a high level in the human ovary and GDNF signaling is involved in the direct control of follicular activation and oocyte maturation. Transforming growth factor-β1 (TGF-β1) plays an important role in the regulation of various ovarian functions. Furin is an intracellular serine endopeptidase of the subtilisin family that is closely associated with the activation of multiple protein precursors. Despite the important roles of GDNF and TGF-β1 in the regulation of follicular development, whether TGF-β is able to regulate the expression and production of GDNF in human granulosa cells remains to be determined. The aim of this study was to investigate the effect of TGF-β1 on the production of GDNF and its underlying mechanisms in human granulosa-lutein (hGL) cells. We used two types of hGL cells (primary hGL cells and an established immortalized hGL cell line, SVOG cells) as study models. Our results show that TGF-β1 significantly induced the expression of GDNF and furin, which, in turn, increased the production of mature GDNF. Using a dual inhibition approach combining RNA interference and kinase inhibitors against cell signaling components, we showed that the TβRII type II receptor and ALK5 type I receptor are the principal receptors that mediated TGF-β1-induced cellular activity in hGL cells. Additionally, Sma- and Mad-related protein (SMAD)3 and SMAD4 are the downstream signaling transducers that mediate the biological response induced by TGF-β1. Furthermore, furin is the main proprotein convertase that induces the production of GDNF. These findings provide additional regulatory mechanisms by which an intrafollicular factor influences the production of another growth factor through a paracrine or autocrine interaction in hGL cells.
Highlights
Purified and cloned in 1993, glia cell line-derived neurotrophic factor (GDNF) is characterized as a critical trophic factor that promotes morphological differentiation and survival of midbrain dopaminergic neurons [1]
The Western blot analysis showed that the same concentrations (1 and 10 ng/mL) of Transforming growth factor-β1 (TGF-β1) induced a similar effect on the protein levels of GDNF after 24 h of treatment (Figure 1B)
We provide the first data showing that TGF-β1 promotes the expression, maturation and secretion of GDNF in human granulosa-lutein (hGL) cells
Summary
Purified and cloned in 1993, glia cell line-derived neurotrophic factor (GDNF) is characterized as a critical trophic factor that promotes morphological differentiation and survival of midbrain dopaminergic neurons [1]. Animal studies have shown that GDNF plays an important role in the positive regulation of follicular growth and the development of preimplantation embryos in pigs and rats [7,9]. Evidence obtained from clinical data reveals that GDNF supplementation increases the number of metaphase II oocytes by promoting oocyte maturation and cumulus cell viability [10,11,12]. Given the important role of GDNF in the modulation of human follicular function, the regulation of GDNF in the human ovary has been a focus of research. It is unclear how GDNF is regulated and the underlying molecular mechanisms in the human ovary
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