TY - JOUR
T1 - Undifferentiated spermatogonia regulate Cyp26b1 expression through NOTCH signaling and drive germ cell differentiation
AU - Parekh, Parag A.
AU - Garcia, Thomas X.
AU - Waheeb, Reham
AU - Jain, Vivek
AU - Gandhi, Pooja
AU - Meistrich, Marvin L.
AU - Shetty, Gunapala
AU - Hofmann, Marie Claude
N1 - Funding Information:
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.
Publisher Copyright:
© FASEB
PY - 2019/7/1
Y1 - 2019/7/1
N2 - 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. FASEB J. 33, 8423–8435 (2019). www.fasebj.org.
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. FASEB J. 33, 8423–8435 (2019). www.fasebj.org.
KW - JAG1
KW - Sertoli cell
KW - spermatogenesis
UR - http://www.scopus.com/inward/record.url?scp=85069237237&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85069237237&partnerID=8YFLogxK
U2 - 10.1096/fj.201802361R
DO - 10.1096/fj.201802361R
M3 - Article
C2 - 30991836
AN - SCOPUS:85069237237
SN - 0892-6638
VL - 33
SP - 8423
EP - 8435
JO - FASEB Journal
JF - FASEB Journal
IS - 7
ER -