Germline Stem Cell Activity Is Sustained by SALL4-Dependent Silencing of Distinct Tumor Suppressor Genes.
Germline Stem Cell Activity Is Sustained by SALL4-Dependent Silencing of Distinct Tumor Suppressor Genes.
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DOI：
10.1016/j.stemcr.2017.08.001
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发表时间：
2017-09-12
影响因子：
5.9
通讯作者：
Hobbs RM
中科院分区：
文献类型：
--
作者：
Chan AL;La HM;Legrand JMD;Mäkelä JA;Eichenlaub M;De Seram M;Ramialison M;Hobbs RM
成年男性持续的精子发生和生殖细胞耗竭后的生育能力恢复依赖于未分化的精原细胞。我们之前证明了转录因子SALL4在精原细胞分化中的关键作用。然而，SALL4是否在精原细胞中具有更广泛的作用仍不清楚，尽管它能够与PLZF（一种维持未分化细胞所需的转录因子）共同调节基因。通过开发诱导敲除模型，我们发现分化而非未分化群体的短期完整性需要SALL4。然而，SALL4缺失与未分化精原细胞的长期功能下降和干细胞驱动再生的中断有关。从机制上讲，SALL4与NuRD共抑制因子相关，抑制肿瘤抑制基因Foxl1和Dusp4的表达。异常的Foxl1激活抑制未分化细胞的生长和存活，而DUSP4抑制自我更新途径。因此，我们揭示了SALL4在维持未分化精原细胞活性中的重要作用，并确定了对种系干细胞功能至关重要的调节途径。SALL4缺失的未分化细胞的长期功能受到损害SALL4直接抑制肿瘤抑制基因Foxl1和Dusp4 Foxl1和Dusp4破坏精原细胞增殖和自我更新途径。在这篇文章中，Hobbs和同事描述了转录因子SALL4在维持睾丸中未分化精原细胞中的关键作用。虽然未分化细胞最初耐受急性Sall4缺失，但随着时间的推移，它们逐渐被耗尽。SALL4通过抑制Dusp4和Foxl1调控未分化细胞的功能，抑制细胞增殖和存活，并在异常表达时阻断自我更新信号。
Sustained spermatogenesis in adult males and fertility recovery following germ cell depletion are dependent on undifferentiated spermatogonia. We previously demonstrated a key role for the transcription factor SALL4 in spermatogonial differentiation. However, whether SALL4 has broader roles within spermatogonia remains unclear despite its ability to co-regulate genes with PLZF, a transcription factor required for undifferentiated cell maintenance. Through development of inducible knockout models, we show that short-term integrity of differentiating but not undifferentiated populations requires SALL4. However, SALL4 loss was associated with long-term functional decline of undifferentiated spermatogonia and disrupted stem cell-driven regeneration. Mechanistically, SALL4 associated with the NuRD co-repressor and repressed expression of the tumor suppressor genes Foxl1 and Dusp4. Aberrant Foxl1 activation inhibited undifferentiated cell growth and survival, while DUSP4 suppressed self-renewal pathways. We therefore uncover an essential role for SALL4 in maintenance of undifferentiated spermatogonial activity and identify regulatory pathways critical for germline stem cell function. Undifferentiated but not differentiating spermatogonia tolerate loss of SALL4 Long-term function of Sall4-deleted undifferentiated cells is compromised SALL4 directly represses the tumor suppressor genes Foxl1 and Dusp4 FOXL1 and DUSP4 disrupt spermatogonial proliferation and self-renewal pathways In this article, Hobbs and colleagues characterize a critical role for the transcription factor SALL4 in maintenance of undifferentiated spermatogonia in the testis. While undifferentiated cells initially tolerated acute Sall4 deletion, they were progressively depleted over time. SALL4 regulated undifferentiated cell function by repressing Dusp4 and Foxl1, which suppressed cell proliferation and survival and blocked self-renewal signals when aberrantly expressed.
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影响因子：
4.5
作者：
Gely-Pernot A;Raverdeau M;Teletin M;Vernet N;Féret B;Klopfenstein M;Dennefeld C;Davidson I;Benoit G;Mark M;Ghyselinck NB
通讯作者：
Ghyselinck NB
影响因子：
64.5
作者：
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影响因子：
5.2
作者：
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影响因子：
23.9
作者：
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通讯作者：
Yoshida, Shosei
影响因子：
23.9
作者：
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通讯作者：
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