PMID- 30991836 OWN - NLM STAT- MEDLINE DCOM- 20200519 LR - 20210213 IS - 1530-6860 (Electronic) IS - 0892-6638 (Print) IS - 0892-6638 (Linking) VI - 33 IP - 7 DP - 2019 Jul TI - Undifferentiated spermatogonia regulate Cyp26b1 expression through NOTCH signaling and drive germ cell differentiation. PG - 8423-8435 LID - 10.1096/fj.201802361R [doi] AB - 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. FAU - Parekh, Parag A AU - Parekh PA AD - Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA. FAU - Garcia, Thomas X AU - Garcia TX AD - Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA. AD - Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA. AD - Department of Biology and Biotechnology, University of Houston-Clear Lake, Houston, Texas, USA. FAU - Waheeb, Reham AU - Waheeb R AD - Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA. AD - Department of Theriogenology, University of Alexandria, Alexandria, Egypt. FAU - Jain, Vivek AU - Jain V AD - Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA. AD - Department of Biology and Biotechnology, University of Houston-Clear Lake, Houston, Texas, USA. FAU - Gandhi, Pooja AU - Gandhi P AD - Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA. FAU - Meistrich, Marvin L AU - Meistrich ML AD - Department of Experimental Radiation Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA. FAU - Shetty, Gunapala AU - Shetty G AD - Department of Experimental Radiation Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA. FAU - Hofmann, Marie-Claude AU - Hofmann MC AD - Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA. LA - eng GR - P30 CA016672/CA/NCI NIH HHS/United States GR - R01 HD081244/HD/NICHD NIH HHS/United States GR - R01 HD095341/HD/NICHD NIH HHS/United States GR - T32 ES007326/ES/NIEHS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20190416 PL - United States TA - FASEB J JT - FASEB journal : official publication of the Federation of American Societies for Experimental Biology JID - 8804484 RN - 0 (Cell Cycle Proteins) RN - 0 (Hey1 protein, mouse) RN - 0 (Jag1 protein, mouse) RN - 0 (Jagged-1 Protein) RN - 0 (Receptors, Notch) RN - 0 (SOX9 Transcription Factor) RN - 0 (SOX9 protein, human) RN - 0 (Steroidogenic Factor 1) RN - 0 (steroidogenic factor 1, mouse) RN - EC 1.14.14.1 (Cyp26b1 protein, mouse) RN - EC 1.14.14.1 (Retinoic Acid 4-Hydroxylase) SB - IM MH - Animals MH - Cell Cycle Proteins/genetics/metabolism MH - *Cell Differentiation MH - *Gene Expression Regulation, Developmental MH - Jagged-1 Protein/genetics/metabolism MH - Male MH - Mice MH - Mice, Transgenic MH - Promoter Regions, Genetic MH - Receptors, Notch/genetics/*metabolism MH - Retinoic Acid 4-Hydroxylase/*biosynthesis/genetics MH - SOX9 Transcription Factor/genetics/metabolism MH - *Signal Transduction MH - Spermatogonia/cytology/*metabolism MH - Steroidogenic Factor 1/genetics/metabolism PMC - PMC6593872 OTO - NOTNLM OT - JAG1 OT - Sertoli cell OT - spermatogenesis COIS- This work was funded by U.S. National Institutes of Health (NIH), Eunice Kennedy Shriver National Institute of Child Health and Human Development Grant R01HD081244 (to M.-C.H.) and M. D. Anderson Cancer Center Core Facilities Support Grant CA16672. The authors declare no conflicts of interest. EDAT- 2019/04/18 06:00 MHDA- 2020/05/20 06:00 PMCR- 2020/04/16 CRDT- 2019/04/18 06:00 PHST- 2019/04/18 06:00 [pubmed] PHST- 2020/05/20 06:00 [medline] PHST- 2019/04/18 06:00 [entrez] PHST- 2020/04/16 00:00 [pmc-release] AID - FJ_201802361R [pii] AID - 10.1096/fj.201802361R [doi] PST - ppublish SO - FASEB J. 2019 Jul;33(7):8423-8435. doi: 10.1096/fj.201802361R. Epub 2019 Apr 16.