TGF-β1 Increases GDNF Production by Upregulating the Expression of GDNF and Furin in Human Granulosa-Lutein Cells

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.

BMP2 increases the production of BDNF through the upregulation of proBDNF and furin expression in human granulosa‐lutein cells

“…27 Our previous studies showed that furin is highly expressed in hGL cells and is involved in the processing and secretion of several intraovarian factors, including activin A, TGF-β1, and glial cell line-derived neurotrophic factor. [28][29][30] Furthermore, we have shown that BMP4 and BMP7 upregulate the expression of furin in hGL cells. 31 In human epithelial cells, furin promotes mature BDNF by cleaving pro-BDNF.…”

“…Previous studies have shown that furin is the corresponding enzyme that processes a variety of cellular factors, including neuropeptides, hormones, growth factors, glycoprotein, receptors, adhesion molecules, and bacterial toxins 27 . Our previous studies showed that furin is highly expressed in hGL cells and is involved in the processing and secretion of several intraovarian factors, including activin A, TGF‐β1, and glial cell line‐derived neurotrophic factor 28‐30 . Furthermore, we have shown that BMP4 and BMP7 upregulate the expression of furin in hGL cells 31 .…”

Regeneration of Cochlear Synapses by Systemic Administration of a Bisphosphonate

“…Third, zoledronate may lead to upregulation of neurotrophic factors, such as glial cell line-derived neurotrophic factor (GDNF) or insulin growth factor-1 (IGF-1). Different bisphosphonates, including zoledronate, upregulate TGF-beta expression ( Jia et al, 2013 ; Manzano-Moreno et al, 2018 ), and TGF-β1 can increase GDNF production by upregulating GDNF and furin gene expression ( Yin et al, 2020 ). Moreover, GDNF overexpression in neuronal progenitors leads to downregulation of four key enzymes of the cholesterol-synthesis pathway, including farnesyl-diphosphate synthetase, resulting in decreased production of farnesyl-pyrophosphate ( Pahnke et al, 2004 ).…”

TGIF1 and SF1 polymorphisms are associated with litter size in Small Tail Han sheep

“…Furthermore, we failed to detect the mutant homozygous genotype TT, and the lethality was the most likely reason for lack of TT genotype (g.37871539C>T) in all sheep breeds. TGIF1 can negatively regulate TGF-β-activated genes such as SMAD2 and SMAD4 (Hu et al, 2011;Hyman et al, 2003;Wotton et al, 1999), and TGF-β/SMAD signalling plays crucial roles in mediating reproduction (Knight & Glister, 2006;Liu, Chang, Yi, Yao, & Leung, 2019;Rossetti et al, 2020;Yin et al, 2020). For example, the disruption of TGF-β/SMAD signalling can cause reproductive problems (Chand et al, 2007), including sterility (Li et al, 2017).…”

“…This suggests that TGIF1 plays a critical role in mammalian reproduction. Studies have also revealed that TGF-β/ SMAD signalling is important in reproductive processes, including in follicular activation (Yin, Chang, Yi, Yao, & Leung, 2020), ovarian follicle development (Knight & Glister, 2006) and oocyte maturation (Yin et al, 2020). Indeed, the inhibition or mutation of key members of the TGF-β/SMAD signalling pathway can cause reproductive problems (Chand, Robertson, Shelling, & Harrison, 2007), including sterility (Li et al, 2017).…”