title: Hierarchical differentiation competence in response to retinoic acid ensures stem cell maintenance during mouse spermatogenesis.
abstract: Stem cells ensure tissue homeostasis through the production of differentiating and self-renewing progeny. In some tissues, this is achieved by the function of a definitive stem cell niche. However, the mechanisms that operate in mouse spermatogenesis are unknown because undifferentiated spermatogonia (Aundiff) are motile and intermingle with differentiating cells in an 'open' niche environment of seminiferous tubules. Aundiff include glial cell line-derived neurotrophic factor receptor α1 (GFRα1)(+) and neurogenin 3 (NGN3)(+) subpopulations, both of which retain the ability to self-renew. However, whereas GFRα1(+) cells comprise the homeostatic stem cell pool, NGN3(+) cells show a higher probability to differentiate into KIT(+) spermatogonia by as yet unknown mechanisms. In the present study, by combining fate analysis of pulse-labeled cells and a model of vitamin A deficiency, we demonstrate that retinoic acid (RA), which may periodically increase in concentration in the tubules during the seminiferous epithelial cycle, induced only NGN3(+) cells to differentiate. Comparison of gene expression revealed that retinoic acid receptor γ (Rarg) was predominantly expressed in NGN3(+) cells, but not in GFRα1(+) cells, whereas the expression levels of many other RA response-related genes were similar in the two populations. Ectopic expression of RARγ was sufficient to induce GFRα1(+) cells to directly differentiate to KIT(+) cells without transiting the NGN3(+) state. Therefore, RARγ plays key roles in the differentiation competence of NGN3(+) cells. We propose a novel mechanism of stem cell fate selection in an open niche environment whereby undifferentiated cells show heterogeneous competence to differentiate in response to ubiquitously distributed differentiation-inducing signals.
authors: Division of Germ Cell Biology, National Institute for Basic Biology, National Institutes of Natural Sciences, 5-1 Higashiyama, Myodaiji, Okazaki 444-8787, Japan Department of Basic Biology, School of Life Science, Graduate University for Advanced Studies (Sokendai), 5-1 Higashiyama, Myodaiji, Okazaki 444-8787, Japan.
authors: Kanako
authors: K
authors: Ikami
authors: Division of Germ Cell Biology, National Institute for Basic Biology, National Institutes of Natural Sciences, 5-1 Higashiyama, Myodaiji, Okazaki 444-8787, Japan Department of Basic Biology, School of Life Science, Graduate University for Advanced Studies (Sokendai), 5-1 Higashiyama, Myodaiji, Okazaki 444-8787, Japan.
authors: Moe
authors: M
authors: Tokue
authors: Division of Germ Cell Biology, National Institute for Basic Biology, National Institutes of Natural Sciences, 5-1 Higashiyama, Myodaiji, Okazaki 444-8787, Japan.
authors: Ryo
authors: R
authors: Sugimoto
authors: Division of Developmental Genetics, Okazaki Institute for Integrative Bioscience, National Institute for Basic Biology, National Institutes of Natural Sciences, 5-1 Higashiyama, Myodaiji, Okazaki 444-8787, Japan.
authors: Chiyo
authors: C
authors: Noda
authors: Department of Basic Biology, School of Life Science, Graduate University for Advanced Studies (Sokendai), 5-1 Higashiyama, Myodaiji, Okazaki 444-8787, Japan Division of Developmental Genetics, Okazaki Institute for Integrative Bioscience, National Institute for Basic Biology, National Institutes of Natural Sciences, 5-1 Higashiyama, Myodaiji, Okazaki 444-8787, Japan.
authors: Satoru
authors: S
authors: Kobayashi
authors: Division of Germ Cell Biology, National Institute for Basic Biology, National Institutes of Natural Sciences, 5-1 Higashiyama, Myodaiji, Okazaki 444-8787, Japan Department of Basic Biology, School of Life Science, Graduate University for Advanced Studies (Sokendai), 5-1 Higashiyama, Myodaiji, Okazaki 444-8787, Japan.
authors: Kenshiro
authors: K
authors: Hara
authors: Division of Germ Cell Biology, National Institute for Basic Biology, National Institutes of Natural Sciences, 5-1 Higashiyama, Myodaiji, Okazaki 444-8787, Japan Department of Basic Biology, School of Life Science, Graduate University for Advanced Studies (Sokendai), 5-1 Higashiyama, Myodaiji, Okazaki 444-8787, Japan shosei@nibb.ac.jp.
authors: Shosei
authors: S
authors: Yoshida
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors / Q000378:metabolism; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D013091:Spermatogenesis / Q000502:physiology*; D013234:Stem Cells / Q000502:physiology*; D014212:Tretinoin / Q000494:pharmacology*; D014802:Vitamin A Deficiency / Q000378:metabolism*; D000097768:Retinoic Acid Receptor gamma
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D009419:Nerve Tissue Proteins; D018168:Receptors, Retinoic Acid; D014212:Tretinoin; D000097768:Retinoic Acid Receptor gamma; C494988:Gfra1 protein, mouse; C407737:Neurog3 protein, mouse
keywords: Retinoic acid receptor gamma; Spermatogenesis; Spermatogonia; Stem cell niche