Tumor suppressor gene Rb is required for self-renewal of spermatogonial stem cells in mice
The retinoblastoma tumor suppressor gene Rb is essential for maintaining the quiescence and for regulating the differentiation of somatic stem cells. Inactivation of Rb in somatic stem cells typically leads to their overexpansion, often followed by increased apoptosis, defective terminal differentia...
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| Format: | Article |
| Language: | en_US |
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National Academy of Sciences (U.S.)
2014
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| Online Access: | http://hdl.handle.net/1721.1/85906 https://orcid.org/0000-0001-9920-3411 |
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| author | Hu, Yueh-Chiang de Rooij, Dirk G. Page, David C |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Hu, Yueh-Chiang de Rooij, Dirk G. Page, David C |
| author_sort | Hu, Yueh-Chiang |
| collection | MIT |
| description | The retinoblastoma tumor suppressor gene Rb is essential for maintaining the quiescence and for regulating the differentiation of somatic stem cells. Inactivation of Rb in somatic stem cells typically leads to their overexpansion, often followed by increased apoptosis, defective terminal differentiation, and tumor formation. However, Rb’s roles in germ-line stem cells have not been explored. We conditionally disrupted the Rb gene in mouse germ cells in vivo and discovered unanticipated consequences for GFRa1-protein-expressing A[subscript single] (GFRa1[superscript +] A[subscript s]) spermatogonia, the major source of male germ-line stem cells. Rb-deficient GFRa1[superscript +] A[subscript s] spermatogonia were present at normal density in testes 5 d after birth, but they lacked the capacity for self-renewal, resulting in germ cell depletion by 2 mo of age. Rb deficiency did not affect the proliferative activity of GFRa1[superscript +] A[subscript s] spermatogonia, but their progeny were exclusively transit-amplifying progenitor spermatogonia and did not include GFRa1[superscript +] A[subscript s] spermatogonia. In addition, Rb deficiency caused prolonged proliferation of progenitor spermatogonia, transiently enlarging this population. Despite these defects, Rb deficiency did not block terminal differentiation into functional sperm; offspring were readily obtained from young males whose germ cell pool was not yet depleted. We conclude that Rb is required for self-renewal of germ-line stem cells, but contrary to its critical roles in somatic stem cells, it is dispensable for their proliferative activity and terminal differentiation. Thus, this study identifies an unexpected function for Rb in maintaining the stem cell pool in the male germ line. |
| first_indexed | 2024-09-23T12:15:53Z |
| format | Article |
| id | mit-1721.1/85906 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T12:15:53Z |
| publishDate | 2014 |
| publisher | National Academy of Sciences (U.S.) |
| record_format | dspace |
| spelling | mit-1721.1/859062022-10-01T08:48:37Z Tumor suppressor gene Rb is required for self-renewal of spermatogonial stem cells in mice Hu, Yueh-Chiang de Rooij, Dirk G. Page, David C Massachusetts Institute of Technology. Department of Biology Whitehead Institute for Biomedical Research Page, David C. The retinoblastoma tumor suppressor gene Rb is essential for maintaining the quiescence and for regulating the differentiation of somatic stem cells. Inactivation of Rb in somatic stem cells typically leads to their overexpansion, often followed by increased apoptosis, defective terminal differentiation, and tumor formation. However, Rb’s roles in germ-line stem cells have not been explored. We conditionally disrupted the Rb gene in mouse germ cells in vivo and discovered unanticipated consequences for GFRa1-protein-expressing A[subscript single] (GFRa1[superscript +] A[subscript s]) spermatogonia, the major source of male germ-line stem cells. Rb-deficient GFRa1[superscript +] A[subscript s] spermatogonia were present at normal density in testes 5 d after birth, but they lacked the capacity for self-renewal, resulting in germ cell depletion by 2 mo of age. Rb deficiency did not affect the proliferative activity of GFRa1[superscript +] A[subscript s] spermatogonia, but their progeny were exclusively transit-amplifying progenitor spermatogonia and did not include GFRa1[superscript +] A[subscript s] spermatogonia. In addition, Rb deficiency caused prolonged proliferation of progenitor spermatogonia, transiently enlarging this population. Despite these defects, Rb deficiency did not block terminal differentiation into functional sperm; offspring were readily obtained from young males whose germ cell pool was not yet depleted. We conclude that Rb is required for self-renewal of germ-line stem cells, but contrary to its critical roles in somatic stem cells, it is dispensable for their proliferative activity and terminal differentiation. Thus, this study identifies an unexpected function for Rb in maintaining the stem cell pool in the male germ line. Howard Hughes Medical Institute 2014-03-24T16:22:50Z 2014-03-24T16:22:50Z 2013-07 2013-04 Article http://purl.org/eprint/type/JournalArticle 0027-8424 1091-6490 http://hdl.handle.net/1721.1/85906 Hu, Y.-C., D. G. de Rooij, and D. C. Page. “Tumor Suppressor Gene Rb Is Required for Self-Renewal of Spermatogonial Stem Cells in Mice.” Proceedings of the National Academy of Sciences 110, no. 31 (July 30, 2013): 12685–12690. https://orcid.org/0000-0001-9920-3411 en_US http://dx.doi.org/10.1073/pnas.1311548110 Proceedings of the National Academy of Sciences Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf National Academy of Sciences (U.S.) National Academy of Science (U.S.) |
| spellingShingle | Hu, Yueh-Chiang de Rooij, Dirk G. Page, David C Tumor suppressor gene Rb is required for self-renewal of spermatogonial stem cells in mice |
| title | Tumor suppressor gene Rb is required for self-renewal of spermatogonial stem cells in mice |
| title_full | Tumor suppressor gene Rb is required for self-renewal of spermatogonial stem cells in mice |
| title_fullStr | Tumor suppressor gene Rb is required for self-renewal of spermatogonial stem cells in mice |
| title_full_unstemmed | Tumor suppressor gene Rb is required for self-renewal of spermatogonial stem cells in mice |
| title_short | Tumor suppressor gene Rb is required for self-renewal of spermatogonial stem cells in mice |
| title_sort | tumor suppressor gene rb is required for self renewal of spermatogonial stem cells in mice |
| url | http://hdl.handle.net/1721.1/85906 https://orcid.org/0000-0001-9920-3411 |
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