Tumor suppressor gene Rb is required for self-renewal of spermatogonial stem cells in mice
Tumor suppressor gene Rb is required for self-renewal of spermatogonial stem cells in mice
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DOI：
10.1073/pnas.1311548110
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发表时间：
2013-07-30
影响因子：
11.1
通讯作者：
Page, David C.
中科院分区：
文献类型：
--
作者：
Hu, Yueh-Chiang;de Rooij, Dirk G.;Page, David C.
视网膜母细胞瘤肿瘤抑制基因Rb对维持体干细胞的静止和调节体干细胞的分化是必需的。体干细胞中Rb的失活通常导致其过度扩增，通常随后是凋亡增加、终末分化缺陷和肿瘤形成。然而，Rb在生殖系干细胞中的作用尚未被探索。我们有条件地破坏了体内小鼠生殖细胞中的Rb基因，并发现了表达GFRa 1蛋白的A（单）（GFRa 1（+）A（s））精原细胞（雄性生殖系干细胞的主要来源）的意外后果。Rb缺陷型GFRa 1（+）A（s）精原细胞在出生后5 d在睾丸中以正常密度存在，但它们缺乏自我更新能力，导致2月龄时生殖细胞耗竭。Rb缺乏不影响GFRa 1（+）A（s）精原细胞的增殖活性，但其子代细胞仅为过渡扩增型祖细胞，不含GFRa 1（+）A（s）精原细胞。此外，Rb缺乏引起祖精原细胞的增殖延长，瞬时扩大这一人口。尽管有这些缺陷，Rb缺乏并不阻止终末分化为功能性精子;后代很容易从生殖细胞库尚未耗尽的年轻男性中获得。我们的结论是，Rb是生殖系干细胞的自我更新所需的，但相反，它在体干细胞中的关键作用，它是其增殖活性和终末分化。因此，这项研究确定了一个意想不到的功能Rb在维持干细胞池中的男性生殖系。
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(single) (GFRa1(+) A(s)) spermatogonia, the major source of male germ-line stem cells. Rb-deficient GFRa1(+) A(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(+) A(s) spermatogonia, but their progeny were exclusively transit-amplifying progenitor spermatogonia and did not include GFRa1(+) A(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.