The transforming growth factor‐β superfamily in early spermatogenesis: potential relevance to testicular dysgenesis

Abstract

Regulated transforming growth factor-beta (TGFbeta) superfamily signalling is an integral part of normal testicular development and the processes that enable the production of fertile sperm. Through shared utilization of receptors, signal transduction components and inhibitors, many ligands in this family exhibit functional overlaps; this facet of their function is critical to understand because these ligands are often co-expressed and, hence, they may compete with or compensate for one another, depending on the specific cellular context. This review describes particular germ cell maturation steps governed by bone morphogenetic proteins, glial cell line-derived neurotrophic factor and activins, focusing on data predominantly from rodent studies that implicate activin and other family members in modulation of gonocyte and spermatogonial stem cell development. We also review knowledge of the TGFbeta superfamily signalling components in the human testis, exploring their potential impact on the processes associated with disrupted gonocyte development and an enhanced risk of testicular cancer.

The crucial role of Activin A on the formation of primordial germ cell-like cells from skin-derived stem cells in vitro

“…Therefore Smad3 may be a key intracellular component of ActA in the induction, possibly mediated by activating ActA receptors, ACTRI and ACTRII. 35 This finding was also confirmed in cells from Smad3 knockout mice.…”

“…33 This is supported by the finding that ActA can promote meiotic initiation in female germ cells in mice, and regulate spermatogenic cell and sertoli cell proliferation and differentiation, along with its functions in germ cell development in vivo and in vitro. 34,35 ActA is thus considered to be an important factor for PGCLC differentiation and development in vitro, as well as meiotic entry.…”

The Blood-Testis Barrier and Its Implications for Male Contraception

“…TGF-␤ exerts its biological effects by first binding to the TGF-␤ type II receptor (T␤RII), which then recruits the type I receptor (T␤RI), forming a TGF-␤/T␤RII/T␤RI complex, except that TGF-␤2 binds to the two receptors almost at the same time with the assistance of the type III receptor, ␤-glycan (Massagué, 2000;Massagué and Gomis, 2006). This protein complex, in turn, recruits other adaptors, mediating different signaling pathways downstream, involving different GTPases and mitogenactivated protein kinases (MAPKs), and regulating an array of cellular events and functions under normal and pathological conditions, including spermatogenesis (Lui et al, 2003a;Xia et al, 2005a;Loveland et al, 2007;Massagué, 2008;Worthington et al, 2011). For instance, TGF-␤ signaling downstream involving either p38 MAPK (Lui et al, 2003c;Wong et al, 2004) or ERK1/2 can disrupt either BTB and germ cell adhesion or BTB function only, respectively.…”

Control of KIT signalling in male germ cells: what can we learn from other systems?

“…Their actions are essential for embryonic development, in particular for germ layer specification and patterning during embryogenesis (Chan & Etkin 2001). The mammalian TGFB superfamily contains w40 known ligand subunits, each forming a dimer to affect signal transduction via a serine/threonine kinase receptor in target cells (Loveland et al 2007, Schmierer & Hill 2007. This includes 3 TGFB isoforms, 4 activin b subunits, nodal, 10 bone morphogenetic proteins (BMPs) and 11 growth differentiation factors (Schmierer & Hill 2007).…”