title: Inhibitor of DNA binding 4 is expressed selectively by single spermatogonia in the male germline and regulates the self-renewal of spermatogonial stem cells in mice.
abstract: Continual spermatogenesis at a quantitatively normal level is required to sustain male fertility. The foundation of this process relies on maintenance of an undifferentiated spermatogonial population consisting of spermatogonial stem cells (SSCs) that self-renew as well as transient amplifying progenitors produced by differentiation. In mammals, type A(single) spermatogonia form the SSC population, but molecular markers distinguishing these from differentiating progenitors are undefined and knowledge of mechanisms regulating their functions is limited. We show that in the mouse male germline the transcriptional repressor ID4 is expressed by a subpopulation of undifferentiated spermatogonia and selectively marks A(single) spermatogonia. In addition, we found that ID4 expression is up-regulated in isolated SSC-enriched fractions by stimulation from GDNF, a key growth factor driving self-renewal. In mice lacking ID4 expression, quantitatively normal spermatogenesis was found to be impaired due to progressive loss of the undifferentiated spermatogonial population during adulthood. Moreover, reduction of ID4 expression by small interfering RNA treatment abolished the ability of wild-type SSCs to expand in vitro during long-term culture without affecting their survival. Collectively, these results indicate that ID4 is a distinguishing marker of SSCs in the mammalian germline and plays an important role in the regulation of self-renewal.
authors.affiliation: Center for Reproductive Biology and Health, Department of Dairy and Animal Science, College of Agricultural Sciences, The Pennsylvania State University, University Park, PA, USA.
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Oatley
authors.forename: Amy V
authors.initials: AV
authors.lastname: Kaucher
authors.forename: Karen E
authors.initials: KE
authors.lastname: Racicot
authors.forename: Jon M
authors.initials: JM
authors.lastname: Oatley
mesh_terms: D000818:Animals; D015415:Biomarkers; D005786:Gene Expression Regulation / Q000502:physiology*; D020868:Gene Silencing; D051796:Inhibitor of Differentiation Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D034741:RNA, Small Interfering; D013093:Spermatogonia / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism*; D013737:Testis / Q000378:metabolism
chemical_list: D015415:Biomarkers; C086479:Idb4 protein, mouse; D051796:Inhibitor of Differentiation Proteins; D034741:RNA, Small Interfering