Identification of EOMES-expressing Spermatogonial Stem Cells and Their Regulation by PLZF

Overview

Journal Elife

Specialty Biology

Date 2019 Jun 1

PMID 31149899

Citations 33

Authors

Manju Sharma

Anuj Srivastava

Heather E Fairfield

David Bergstrom

William F Flynn

Robert E Braun

Affiliations

Soon will be listed here.

Abstract

Long-term maintenance of spermatogenesis in mammals is supported by GDNF, an essential growth factor required for spermatogonial stem cell (SSC) self-renewal. Exploiting a transgenic GDNF overexpression model, which expands and normalizes the pool of undifferentiated spermatogonia between and mice, we used RNAseq to identify a rare subpopulation of cells that express EOMES, a T-box transcription factor. Lineage tracing and busulfan challenge show that these are SSCs that contribute to steady state spermatogenesis as well as regeneration following chemical injury. EOMES+ SSCs have a lower proliferation index in wild-type than in mice, suggesting that PLZF regulates their proliferative activity and that EOMES+ SSCs are lost through proliferative exhaustion in mice. Single cell RNA sequencing of EOMES+ cells from and mice support the conclusion that SSCs are hierarchical yet heterogeneous.

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References

Costoya J, Hobbs R, Barna M, Cattoretti G, Manova K, Sukhwani M . Essential role of Plzf in maintenance of spermatogonial stem cells. Nat Genet. 2004; 36(6):653-9. DOI: 10.1038/ng1367. View

de Rooij D, Lok D, Weenk D . Feedback regulation of the proliferation of the undifferentiated spermatogonia in the Chinese hamster by the differentiating spermatogonia. Cell Tissue Kinet. 1985; 18(1):71-81. DOI: 10.1111/j.1365-2184.1985.tb00633.x. View

Cheshier S, Morrison S, Liao X, Weissman I . In vivo proliferation and cell cycle kinetics of long-term self-renewing hematopoietic stem cells. Proc Natl Acad Sci U S A. 1999; 96(6):3120-5. PMC: 15905. DOI: 10.1073/pnas.96.6.3120. View

Ball H, Melnick A, Shaknovich R, Kohanski R, Licht J . The promyelocytic leukemia zinc finger (PLZF) protein binds DNA in a high molecular weight complex associated with cdc2 kinase. Nucleic Acids Res. 1999; 27(20):4106-13. PMC: 148680. DOI: 10.1093/nar/27.20.4106. View

Hermann B, Sukhwani M, Hansel M, Orwig K . Spermatogonial stem cells in higher primates: are there differences from those in rodents?. Reproduction. 2009; 139(3):479-93. PMC: 2895987. DOI: 10.1530/REP-09-0255. View

Goldberg E, Eddy E, Duan C, Odet F . LDHC: the ultimate testis-specific gene. J Androl. 2009; 31(1):86-94. PMC: 2915756. DOI: 10.2164/jandrol.109.008367. View

Costello I, Pimeisl I, Drager S, Bikoff E, Robertson E, Arnold S . The T-box transcription factor Eomesodermin acts upstream of Mesp1 to specify cardiac mesoderm during mouse gastrulation. Nat Cell Biol. 2011; 13(9):1084-91. PMC: 4531310. DOI: 10.1038/ncb2304. View

Suzuki H, Sada A, Yoshida S, Saga Y . The heterogeneity of spermatogonia is revealed by their topology and expression of marker proteins including the germ cell-specific proteins Nanos2 and Nanos3. Dev Biol. 2009; 336(2):222-31. DOI: 10.1016/j.ydbio.2009.10.002. View

Kehler J, Tolkunova E, Koschorz B, Pesce M, Gentile L, Boiani M . Oct4 is required for primordial germ cell survival. EMBO Rep. 2004; 5(11):1078-83. PMC: 1299174. DOI: 10.1038/sj.embor.7400279. View

10.

Spangrude G, Heimfeld S, Weissman I . Purification and characterization of mouse hematopoietic stem cells. Science. 1988; 241(4861):58-62. DOI: 10.1126/science.2898810. View

11.

Yoshida S, Takakura A, Ohbo K, Abe K, Wakabayashi J, Yamamoto M . Neurogenin3 delineates the earliest stages of spermatogenesis in the mouse testis. Dev Biol. 2004; 269(2):447-58. DOI: 10.1016/j.ydbio.2004.01.036. View

12.

Nakagawa T, Sharma M, Nabeshima Y, Braun R, Yoshida S . Functional hierarchy and reversibility within the murine spermatogenic stem cell compartment. Science. 2010; 328(5974):62-7. PMC: 2981100. DOI: 10.1126/science.1182868. View

13.

Madisen L, Zwingman T, Sunkin S, Oh S, Zariwala H, Gu H . A robust and high-throughput Cre reporting and characterization system for the whole mouse brain. Nat Neurosci. 2009; 13(1):133-40. PMC: 2840225. DOI: 10.1038/nn.2467. View

14.

Shaknovich R, Yeyati P, Ivins S, Melnick A, Lempert C, Waxman S . The promyelocytic leukemia zinc finger protein affects myeloid cell growth, differentiation, and apoptosis. Mol Cell Biol. 1998; 18(9):5533-45. PMC: 109138. DOI: 10.1128/MCB.18.9.5533. View

15.

Grasso M, Fuso A, Dovere L, de Rooij D, Stefanini M, Boitani C . Distribution of GFRA1-expressing spermatogonia in adult mouse testis. Reproduction. 2011; 143(3):325-32. DOI: 10.1530/REP-11-0385. View

16.

Patel R, Jain M . NGS QC Toolkit: a toolkit for quality control of next generation sequencing data. PLoS One. 2012; 7(2):e30619. PMC: 3270013. DOI: 10.1371/journal.pone.0030619. View

17.

van Keulen C, de Rooij D . Spermatogonial stem cell renewal in the mouse. II. After cell loss. Cell Tissue Kinet. 1973; 6(4):337-45. DOI: 10.1111/j.1365-2184.1973.tb01622.x. View

18.

Chakraborty P, Buaas F, Sharma M, Snyder E, de Rooij D, Braun R . LIN28A marks the spermatogonial progenitor population and regulates its cyclic expansion. Stem Cells. 2014; 32(4):860-73. PMC: 4151563. DOI: 10.1002/stem.1584. View

19.

Nakagawa T, Nabeshima Y, Yoshida S . Functional identification of the actual and potential stem cell compartments in mouse spermatogenesis. Dev Cell. 2007; 12(2):195-206. DOI: 10.1016/j.devcel.2007.01.002. View

20.

Tokue M, Ikami K, Mizuno S, Takagi C, Miyagi A, Takada R . SHISA6 Confers Resistance to Differentiation-Promoting Wnt/β-Catenin Signaling in Mouse Spermatogenic Stem Cells. Stem Cell Reports. 2017; 8(3):561-575. PMC: 5355566. DOI: 10.1016/j.stemcr.2017.01.006. View