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However, the mechanisms that operate in mouse spermatogenesis are unknown because undifferentiated spermatogonia (Aundiff) are motile and intermingle with differentiating cells in an \u2018open\u2019 niche environment of seminiferous tubules. Aundiff include glial cell line-derived neurotrophic factor receptor \u03b11 (GFR\u03b11)+ and neurogenin 3 (NGN3)+ subpopulations, both of which retain the ability to self-renew. However, whereas GFR\u03b11+ 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 \u03b3 (Rarg) was predominantly expressed in NGN3+ cells, but not in GFR\u03b11+ cells, whereas the expression levels of many other RA response-related genes were similar in the two populations. Ectopic expression of RAR\u03b3 was sufficient to induce GFR\u03b11+ cells to directly differentiate to KIT+ cells without transiting the NGN3+ state. Therefore, RAR\u03b3 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.<\/jats:p>","DOI":"10.1242\/dev.118695","type":"journal-article","created":{"date-parts":[[2015,4,10]],"date-time":"2015-04-10T01:24:44Z","timestamp":1428629084000},"source":"Crossref","is-referenced-by-count":82,"title":["Hierarchical differentiation competence in response to retinoic acid ensures stem cell maintenance during mouse spermatogenesis"],"prefix":"10.1242","author":[{"given":"Kanako","family":"Ikami","sequence":"first","affiliation":[{"name":"Division of Germ Cell Biology, National Institute for Basic Biology, National Institutes of Natural Sciences, 5-1 Higashiyama, Myodaiji, Okazaki 444-8787, Japan"},{"name":"Department of Basic Biology, School of Life Science, Graduate University for Advanced Studies (Sokendai), 5-1 Higashiyama, Myodaiji, Okazaki 444-8787, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moe","family":"Tokue","sequence":"additional","affiliation":[{"name":"Division of Germ Cell Biology, National Institute for Basic Biology, National Institutes of Natural Sciences, 5-1 Higashiyama, Myodaiji, Okazaki 444-8787, Japan"},{"name":"Department of Basic Biology, School of Life Science, Graduate University for Advanced Studies (Sokendai), 5-1 Higashiyama, Myodaiji, Okazaki 444-8787, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryo","family":"Sugimoto","sequence":"additional","affiliation":[{"name":"Division of Germ Cell Biology, National Institute for Basic Biology, National Institutes of Natural Sciences, 5-1 Higashiyama, Myodaiji, Okazaki 444-8787, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiyo","family":"Noda","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoru","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"Department of Basic Biology, School of Life Science, Graduate University for Advanced Studies (Sokendai), 5-1 Higashiyama, Myodaiji, Okazaki 444-8787, Japan"},{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenshiro","family":"Hara","sequence":"additional","affiliation":[{"name":"Division of Germ Cell Biology, National Institute for Basic Biology, National Institutes of Natural Sciences, 5-1 Higashiyama, Myodaiji, Okazaki 444-8787, Japan"},{"name":"Department of Basic Biology, School of Life Science, Graduate University for Advanced Studies (Sokendai), 5-1 Higashiyama, Myodaiji, Okazaki 444-8787, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shosei","family":"Yoshida","sequence":"additional","affiliation":[{"name":"Division of Germ Cell Biology, National Institute for Basic Biology, National Institutes of Natural Sciences, 5-1 Higashiyama, Myodaiji, Okazaki 444-8787, Japan"},{"name":"Department of Basic Biology, School of Life Science, Graduate University for Advanced Studies (Sokendai), 5-1 Higashiyama, Myodaiji, Okazaki 444-8787, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2021042608225729200_DEV118695C1","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1016\/S0006-291X(05)81062-9","article-title":"Retinoic acid and synthetic analogs differentially activate retinoic acid receptor dependent transcription","volume":"173","author":"Astrom","year":"1990","journal-title":"Biochem. 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