Undifferentiated spermatogonia regulate <i>Cyp26b1</i> expression through NOTCH signaling and drive germ cell differentiation

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 <i>Cyp26b1</i> expression in postnatal Sertoli cells, the main components of the stem cell niche, are so far unknown. During gonad development, expression of <i>Cyp26b1</i> 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 <i>via</i> direct binding to the <i>Cyp26b1</i> promoter and thus inhibits its expression in Sertoli cells. Further, using <i>in vivo</i> 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 <i>Cyp26b1</i> expression through NOTCH signaling and drive germ cell differentiation.