TY - JOUR
T1 - Constitutive activation of NOTCH1 signaling in Sertoli cells causes gonocyte exit from quiescence
AU - Garcia, Thomas Xavier
AU - DeFalco, Tony
AU - Capel, Blanche
AU - Hofmann, Marie Claude
N1 - Funding Information:
We thank Dr. Lori T. Raetzman (University of Illinois) for the Gt(Rosa)26Sor tm1(Notch1)Dam /J mouse; Dr. Paul S. Cooke (University of Florida) for the Tg(AMH-cre)1Flor mouse; Dr. Rex A. Hess (University of Illinois) for providing histological expertise; Dr. Michael D. Griswold (Washington State University) for the anti-STRA8 antibody; Daryl D. Meling (University of Illinois) for mouse breeding and genotyping; and Anirudh Saraswathula (Duke University) for help with the TNR-GFP testis samples. This study was funded by NIH HD044543 and HD054607 to MCH, NIH F32 HD058433 fellowship to TD, NIH HD39963 and support from the March of Dimes to BC, and NIH T32 ES007326 fellowship to TXG.
PY - 2013/5/1
Y1 - 2013/5/1
N2 - Notch signaling components have long been detected in Sertoli and germ cells in the developing and mature testis. However, the role of this pathway in testis development and spermatogenesis remains unknown. Using reporter mice expressing green fluorescent protein following Notch receptor activation, we found that Notch signaling was active in Sertoli cells at various fetal, neonatal, and adult stages. Since Notch signaling specifies stem cell fate in many developing and mature organ systems, we hypothesized that maintenance and differentiation of gonocytes and/or spermatogonial stem cells would be modulated through this pathway in Sertoli cells. To this end, we generated mutant mice constitutively expressing the active, intracellular domain of NOTCH1 (NICD1) in Sertoli cells. We found that mutant Sertoli cells were morphologically normal before and after birth, but presented a number of functional changes that drastically affected gonocyte numbers and physiology. We observed aberrant exit of gonocytes from mitotic arrest, migration toward cord periphery, and premature differentiation before birth. These events, presumably unsupported by the cellular microenvironment, were followed by gonocyte apoptosis and near complete disappearance of the gonocytes by day 2 after birth. Molecular analysis demonstrated that these effects are correlated with a dysregulation of Sertoli-expressed genes that are required for germ cell maintenance, such as Cyp26b1 and Gdnf. Taken together, our results demonstrate that Notch signaling is active in Sertoli cells throughout development and that proper regulation of Notch signaling in Sertoli cells is required for the maintenance of gonocytes in an undifferentiated state during fetal development.
AB - Notch signaling components have long been detected in Sertoli and germ cells in the developing and mature testis. However, the role of this pathway in testis development and spermatogenesis remains unknown. Using reporter mice expressing green fluorescent protein following Notch receptor activation, we found that Notch signaling was active in Sertoli cells at various fetal, neonatal, and adult stages. Since Notch signaling specifies stem cell fate in many developing and mature organ systems, we hypothesized that maintenance and differentiation of gonocytes and/or spermatogonial stem cells would be modulated through this pathway in Sertoli cells. To this end, we generated mutant mice constitutively expressing the active, intracellular domain of NOTCH1 (NICD1) in Sertoli cells. We found that mutant Sertoli cells were morphologically normal before and after birth, but presented a number of functional changes that drastically affected gonocyte numbers and physiology. We observed aberrant exit of gonocytes from mitotic arrest, migration toward cord periphery, and premature differentiation before birth. These events, presumably unsupported by the cellular microenvironment, were followed by gonocyte apoptosis and near complete disappearance of the gonocytes by day 2 after birth. Molecular analysis demonstrated that these effects are correlated with a dysregulation of Sertoli-expressed genes that are required for germ cell maintenance, such as Cyp26b1 and Gdnf. Taken together, our results demonstrate that Notch signaling is active in Sertoli cells throughout development and that proper regulation of Notch signaling in Sertoli cells is required for the maintenance of gonocytes in an undifferentiated state during fetal development.
KW - CYP26B1
KW - GDNF
KW - Gonocyte
KW - Notch signaling
KW - Sertoli cell
KW - Testis development
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U2 - 10.1016/j.ydbio.2013.01.031
DO - 10.1016/j.ydbio.2013.01.031
M3 - Article
C2 - 23391689
AN - SCOPUS:84876336801
SN - 0012-1606
VL - 377
SP - 188
EP - 201
JO - Developmental Biology
JF - Developmental Biology
IS - 1
ER -