title: Distinct germline progenitor subsets defined through Tsc2-mTORC1 signaling.
abstract: Adult tissue maintenance is often dependent on resident stem cells; however, the phenotypic and functional heterogeneity existing within this self-renewing population is poorly understood. Here, we define distinct subsets of undifferentiated spermatogonia (spermatogonial progenitor cells; SPCs) by differential response to hyperactivation of mTORC1, a key growth-promoting pathway. We find that conditional deletion of the mTORC1 inhibitor Tsc2 throughout the SPC pool using Vasa-Cre promotes differentiation at the expense of self-renewal and leads to germline degeneration. Surprisingly, Tsc2 ablation within a subset of SPCs using Stra8-Cre did not compromise SPC function. SPC activity also appeared unaffected by Amh-Cre-mediated Tsc2 deletion within somatic cells of the niche. Importantly, we find that differentiation-prone SPCs have elevated mTORC1 activity when compared to SPCs with high self-renewal potential. Moreover, SPCs insensitive to Tsc2 deletion are preferentially associated with mTORC1-active committed progenitor fractions. We therefore delineate SPC subsets based on differential mTORC1 activity and correlated sensitivity to Tsc2 deletion. We propose that mTORC1 is a key regulator of SPC fate and defines phenotypically distinct SPC subpopulations with varying propensities for self-renewal and differentiation.
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center Harvard Medical School, Boston, MA, USA Australian Regenerative Medicine Institute and Department of Anatomy and Developmental Biology Monash University, Clayton, VIC, Australia ppandolf@bidmc.harvard.edu robin.hobbs@monash.edu.
authors.forename: Robin M
authors.initials: RM
authors.lastname: Hobbs
authors.affiliation: Australian Regenerative Medicine Institute and Department of Anatomy and Developmental Biology Monash University, Clayton, VIC, Australia.
authors.forename: Hue M
authors.initials: HM
authors.lastname: La
authors.affiliation: Australian Regenerative Medicine Institute and Department of Anatomy and Developmental Biology Monash University, Clayton, VIC, Australia.
authors.forename: Juho-Antti
authors.initials: JA
authors.lastname: Mäkelä
authors.affiliation: Department of Pathology and Oncology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kobayashi
authors.affiliation: Department of Cell Biology, JFCR Cancer Institute, Tokyo, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Noda
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center Harvard Medical School, Boston, MA, USA ppandolf@bidmc.harvard.edu robin.hobbs@monash.edu.
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D053687:Adult Stem Cells / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage / Q000235:genetics*; D049109:Cell Proliferation; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation; D005818:Genetic Engineering; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D046912:Multiprotein Complexes; C102019:Stra8 protein, mouse; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; C045073:Cre recombinase; D019426:Integrases; C090864:Ddx4 protein, mouse; D053487:DEAD-box RNA Helicases
keywords: differentiation; germline stem cells; mTORC1