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

Abstract

The KIT ligand (KITL)/KIT-signalling system is among several pathways known to be essential for fertility. In the postnatal testis, the KIT/KITL interaction is crucial for spermatogonial proliferation, differentiation, survival and subsequent entry into meiosis. Hence, identification of endogenous factors that regulate KIT synthesis is important for understanding the triggers driving germ cell maturation. Although limited information is available regarding local factors in the testicular microenvironment that modulate KIT synthesis at the onset of spermatogenesis, knowledge from other systems could be used as a basis for identifying how KIT function is regulated in germ cells. This review describes the known regulators of KIT, including transcription factors implicated in KIT promoter regulation. In addition, specific downstream outcomes in biological processes that KIT orchestrates are addressed. These are discussed in relationship to current knowledge of mammalian germ cell development.

Endothelial Smad4 restrains the transition to hematopoietic progenitors via suppression of ERK activation

“…It has been reported that certain TGF-b superfamily members modulate c-Kit expression in different systems. 35 For other TGF-b family members and antagonists, including activin A, TGF-b1, SB-431542, and Noggin, none of them showed an apparent influence on embryonic c-Kit expression (supplemental Figure 8A-B).…”

An oncofetal and developmental perspective on testicular germ cell cancer

“…The soluble form is initially bound to the cell membrane, but contains an additional 6th exon encoding an extracellular cleavage site. Both forms activate KIT, but with qualitative and quantitative differences [310] [42,310,[312][313][314]. In the embryonic phase the guidance of KIT positive PGCs from the hind gut epithelium to the gonads depends strongly on KITLG mediated chemo attraction [43,313,315,316].…”

“…Both forms activate KIT, but with qualitative and quantitative differences [310] [42,310,[312][313][314]. In the embryonic phase the guidance of KIT positive PGCs from the hind gut epithelium to the gonads depends strongly on KITLG mediated chemo attraction [43,313,315,316]. KIT or KITLG mutant mice show normal establishment of the germ cell lineage in het hind gut, but aberrant proliferation and unsuccessful migration during embryogenesis [42,310].…”

“…The postnatal testis. In the postnatal testis KIT-KITLG signaling takes place via paracrine signaling in the germline stem cell niche and is crucial for spermatogenesis from the prespermatogonial stage onwards [310,313,[325][326][327]. Spermatogonia are positive for KIT, as are Leydig cells in which KIT signaling triggers testosterone production [313,328].…”

Mouse models of testicular germ cell tumors

“…Huang et al, 1992). In addition of their essential role during migration, the interaction of KITLG with its receptor leads to the dimerization of KIT and its auto-phosphorylation activates two major pathways: (1) the PI3K/AKT signaling cascade regulates transcription of mitotic inhibitors such as CDKN1a, CDKN1b and cyclin D1, and enhances the translational factor eIF4E; (2) the MAPK pathway regulates factors involved in pluripotency such as NANOG and SOX2, and in proliferation (Mithraprabhu & Loveland, 2009). By acting on TRP53 activity, KIT/KITLG pathway controls apoptosis of PGCs by regulating the BCL2 components (i.e.…”