ABSTRACT
Cytochrome P450 family 26 subfamily B member 1 (CYP26B1) regulates the concentration of all-trans retinoic acid (RA) and plays a key role in germ cell differentiation by controlling local distribution of RA. The mechanisms regulating Cyp26b1 expression in postnatal Sertoli cells, the main components of the stem cell niche, are so far unknown. During gonad development, expression of Cyp26b1 is maintained by Steroidogenic Factor 1 (SF-1) and Sex-Determining Region Y Box-9 (SOX9), which ensure that RA is degraded and germ cell differentiation is blocked. Here, we show that the NOTCH target Hairy/Enhancer-of-Split Related with YRPW Motif 1 (HEY1), a transcriptional repressor, regulates germ cell differentiation via direct binding to the Cyp26b1 promoter and thus inhibits its expression in Sertoli cells. Further, using in vivo germ cell ablation, we demonstrate that undifferentiated type A spermatogonia are the cells that activate NOTCH signaling in Sertoli cells through their expression of the NOTCH ligand JAGGED-1 (JAG1) at stage VIII of the seminiferous epithelium cycle, therefore mediating germ cell differentiation by a ligand concentration-dependent process. These data therefore provide more insights into the mechanisms of germ cell differentiation after birth and potentially explain the spatiotemporal RA pulses driving the transition between undifferentiated to differentiating spermatogonia.-Parekh, P. A., Garcia, T. X., Waheeb, R., Jain, V., Gandhi, P., Meistrich, M. L., Shetty, G., Hofmann, M.-C. Undifferentiated spermatogonia regulate Cyp26b1 expression through NOTCH signaling and drive germ cell differentiation.
Subject(s)
Cell Differentiation , Gene Expression Regulation, Developmental , Receptors, Notch/metabolism , Retinoic Acid 4-Hydroxylase/biosynthesis , Signal Transduction , Spermatogonia/metabolism , Animals , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Jagged-1 Protein/genetics , Jagged-1 Protein/metabolism , Male , Mice , Mice, Transgenic , Promoter Regions, Genetic , Receptors, Notch/genetics , Retinoic Acid 4-Hydroxylase/genetics , SOX9 Transcription Factor/genetics , SOX9 Transcription Factor/metabolism , Spermatogonia/cytology , Steroidogenic Factor 1/genetics , Steroidogenic Factor 1/metabolismABSTRACT
Sertoli cells regulate male germ cell proliferation and differentiation and are a critical component of the spermatogonial stem cell (SSC) niche, where homeostasis is maintained by the interplay of several signaling pathways and growth factors. These factors are secreted by Sertoli cells located within the seminiferous epithelium, and by interstitial cells residing between the seminiferous tubules. Sertoli cells and peritubular myoid cells produce glial cell line-derived neurotrophic factor (GDNF), which binds to the RET/GFRA1 receptor complex at the surface of undifferentiated spermatogonia. GDNF is known for its ability to drive SSC self-renewal and proliferation of their direct cell progeny. Even though the effects of GDNF are well studied, our understanding of the regulation its expression is still limited. The purpose of this review is to discuss how GDNF expression in Sertoli cells is modulated within the niche, and how these mechanisms impact germ cell homeostasis.
Subject(s)
Cell Differentiation , Cell Self Renewal , Glial Cell Line-Derived Neurotrophic Factor/metabolism , Sertoli Cells/cytology , Spermatogonia/cytology , Stem Cell Niche , Stem Cells/cytology , Animals , Humans , Male , Sertoli Cells/metabolism , Spermatogonia/metabolism , Stem Cells/metabolismABSTRACT
Biomarkers are at the cornerstone of preventive measures and contribute to the screening process. More recently, biomarkers have been used to gauge the biological response to the employed therapies. Since it is ubiquitously used to detect subclinical disease process, biomarkers also have found its place in cancer therapy related cardiac dysfunction (CTRCD). The aim of this review is to comprehensively present up-to-date knowledge of biomarkers in CTRCD and highlight some of the future biomedical technologies that may strengthen the screening process, and/or provide new insight in pathological mechanisms behind CTRCD.
