title: Mammalian target of rapamycin complex 1 (mTORC1) Is required for mouse spermatogonial differentiation in vivo.
abstract: Spermatogonial stem cells (SSCs) must balance self-renewal with production of transit-amplifying progenitors that differentiate in response to retinoic acid (RA) before entering meiosis. This self-renewal vs. differentiation spermatogonial fate decision is critical for maintaining tissue homeostasis, as imbalances cause spermatogenesis defects that can lead to human testicular cancer or infertility. A great deal of effort has been exerted to understand how the SSC population is maintained. In contrast, little is known about the essential program of differentiation initiated by retinoic acid (RA) that precedes meiosis, and the pathways and proteins involved are poorly defined. We recently reported a novel role for RA in stimulating the PI3/AKT/mTOR kinase signaling pathway to activate translation of repressed mRNAs such as Kit. Here, we examined the requirement for mTOR complex 1 (mTORC1) in mediating the RA signal to direct spermatogonial differentiation in the neonatal testis. We found that in vivo inhibition of mTORC1 by rapamycin blocked spermatogonial differentiation, which led to an accumulation of undifferentiated spermatogonia. In addition, rapamycin also blocked the RA-induced translational activation of mRNAs encoding KIT, SOHLH1, and SOHLH2 without affecting expression of STRA8. These findings highlight dual roles for RA in germ cell development - transcriptional activation of genes, and kinase signaling to stimulate translation of repressed messages required for spermatogonial differentiation.
authors.affiliation: Department of Anatomy and Cell Biology, East Carolina University, Greenville, NC, USA.
authors.forename: Jonathan T
authors.initials: JT
authors.lastname: Busada
authors.affiliation: Department of Anatomy and Cell Biology, East Carolina University, Greenville, NC, USA.
authors.forename: Bryan A
authors.initials: BA
authors.lastname: Niedenberger
authors.affiliation: Department of Anatomy and Cell Biology, East Carolina University, Greenville, NC, USA.
authors.forename: Ellen K
authors.initials: EK
authors.lastname: Velte
authors.affiliation: Department of Biochemistry and Molecular Biology, East Carolina University, Greenville, NC, USA.
authors.forename: Brett D
authors.initials: BD
authors.lastname: Keiper
authors.affiliation: Department of Anatomy and Cell Biology, East Carolina University, Greenville, NC, USA; East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC, USA. Electronic address: geyerc@ecu.edu.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Geyer
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D002454:Cell Differentiation; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000502:physiology*; D020123:Sirolimus / Q000494:pharmacology; D013093:Spermatogonia / Q000166:cytology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D013737:Testis / Q000187:drug effects / Q000473:pathology; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051792:Basic Helix-Loop-Helix Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D014212:Tretinoin; C511466:Sohlh1 protein, mouse; C102019:Stra8 protein, mouse
keywords: Retinoic acid; Spermatogenesis; Spermatogonia; Testis; Translation; mTOR