title: Responses to glial cell line-derived neurotrophic factor change in mice as spermatogonial stem cells form progenitor spermatogonia which replicate and give rise to more differentiated progeny.
abstract: Spermatogonial stem cells (SSCs) are the foundation of spermatogenesis. These cells are classically defined as a subset of morphologically defined A single (As) spermatogonia, which can produce more SSCs or they can give rise to nonstem As cells that, upon replication, generate A paired (Apr) and then A aligned (Aal) spermatogonia. These latter two cell types, along with the nonstem As cells, function as transit-amplifying progenitor cells. It is known that glial cell line-derived neurotrophic factor (GDNF) is essential for maintaining all of these cells, but it is unknown if or how the responses of these cells change as they progress down the pathway to differentiated type A1 spermatogonia. We address this issue by using a chemical-genetic approach to inhibit GDNF signaling in vivo and an in vitro approach to increase GDNF stimulation. We show that inhibition for 2 days suppresses replication of As, Apr, and Aal spermatogonia to an equal extent, whereas stimulation by GDNF preferentially increases replication of As and Apr spermatogonia. We also test if inhibiting GDNF signaling causes As, Apr, and Aal spermatogonia to express Kit, an essential step in their differentiation into type A1 spermatogonia. Inhibition for 3 or 7 days produces a progressive increase in the percentages of As, Apr, and Aal undergoing differentiation, with the largest increase observed in Aal spermatogonia. Finally, we demonstrate that numbers of SSCs decrease more slowly than numbers of progenitor spermatogonia when GDNF signaling is inhibited. Taken together, these data suggest that there are significant changes in the responses to GDNF as SSCs give rise to progenitor spermatogonia, which replicate and gradually differentiate into type A1 spermatogonia.
authors.affiliation: Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
authors.forename: Nicole
authors.initials: N
authors.lastname: Parker
authors.affiliation: Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
authors.forename: Hayley
authors.initials: H
authors.lastname: Falk
authors.affiliation: Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
authors.forename: Dolly
authors.initials: D
authors.lastname: Singh
authors.affiliation: Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
authors.forename: Anthony
authors.initials: A
authors.lastname: Fidaleo
authors.affiliation: Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Smith
authors.affiliation: Department of Cellular and Molecular Pharmacology and Howard Hughes Medical Institute, University of California San Francisco, San Francisco, California.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Lopez
authors.affiliation: Department of Cellular and Molecular Pharmacology and Howard Hughes Medical Institute, University of California San Francisco, San Francisco, California.
authors.forename: Kevan M
authors.initials: KM
authors.lastname: Shokat
authors.affiliation: Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland wwright@jhsph.edu.
authors.forename: William W
authors.initials: WW
authors.lastname: Wright
mesh_terms: D053687:Adult Stem Cells / Q000166:cytology* / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D005786:Gene Expression Regulation / Q000502:physiology; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000494:pharmacology*; D008297:Male; D051379:Mice; D012671:Seminiferous Tubules / Q000166:cytology; D015398:Signal Transduction; D046509:Tissue Culture Techniques
chemical_list: D051100:Glial Cell Line-Derived Neurotrophic Factor
keywords: GDNF; Ret; progenitor spermatogonia; spermatogonial stem cells