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OvoL/Shavenbaby 依赖性类固醇开关控制肠道干细胞的自我更新与分化。

Steroid-dependent switch of OvoL/Shavenbaby controls self-renewal versus differentiation of intestinal stem cells.

机构信息

Faculty of Sciences III, Lebanese University, Tripoli, Lebanon.

Azm Center for Research in Biotechnology and its Applications, LBA3B, EDST, Lebanese University, Tripoli, Lebanon.

出版信息

EMBO J. 2021 Feb 15;40(4):e104347. doi: 10.15252/embj.2019104347. Epub 2020 Dec 29.

DOI:10.15252/embj.2019104347
PMID:33372708
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7883054/
Abstract

Adult stem cells must continuously fine-tune their behavior to regenerate damaged organs and avoid tumors. While several signaling pathways are well known to regulate somatic stem cells, the underlying mechanisms remain largely unexplored. Here, we demonstrate a cell-intrinsic role for the OvoL family transcription factor, Shavenbaby (Svb), in balancing self-renewal and differentiation of Drosophila intestinal stem cells. We find that svb is a downstream target of Wnt and EGFR pathways, mediating their activity for stem cell survival and proliferation. This requires post-translational processing of Svb into a transcriptional activator, whose upregulation induces tumor-like stem cell hyperproliferation. In contrast, the unprocessed form of Svb acts as a repressor that imposes differentiation into enterocytes, and suppresses tumors induced by altered signaling. We show that the switch between Svb repressor and activator is triggered in response to systemic steroid hormone, which is produced by ovaries. Therefore, the Svb axis allows intrinsic integration of local signaling cues and inter-organ communication to adjust stem cell proliferation versus differentiation, suggesting a broad role of OvoL/Svb in adult and cancer stem cells.

摘要

成体干细胞必须不断微调其行为，以再生受损的器官并避免肿瘤。虽然有几个信号通路被认为可以调节体干细胞，但潜在的机制在很大程度上仍未被探索。在这里，我们证明了 OvoL 家族转录因子 Shavenbaby（Svb）在平衡果蝇肠道干细胞的自我更新和分化中的细胞内作用。我们发现，svb 是 Wnt 和 EGFR 途径的下游靶标，介导它们对干细胞存活和增殖的活性。这需要 Svb 的翻译后加工成转录激活剂，其上调诱导类似于肿瘤的干细胞过度增殖。相比之下，未加工形式的 Svb 作为一种抑制因子，促使分化为肠细胞，并抑制由信号改变引起的肿瘤。我们表明，Svb 抑制剂和激活剂之间的转换是响应由卵巢产生的全身性类固醇激素而触发的。因此，Svb 轴允许内在整合局部信号线索和器官间通讯，以调节干细胞增殖与分化，这表明 OvoL/Svb 在成人和癌症干细胞中具有广泛的作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5518/7883054/029b0ed0f376/EMBJ-40-e104347-g014.jpg
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