Ligand-independent activation of the Hedgehog pathway displays non-cell autonomous proliferation during eye development in Drosophila.
Ligand-independent activation of the Hedgehog pathway displays non-cell autonomous proliferation during eye development in Drosophila.
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DOI：
10.1016/j.mod.2012.05.009
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发表时间：
2012-07
影响因子：
2.6
通讯作者：
Bergmann, Andreas
中科院分区：
文献类型：
--
作者：
Christiansen, Audrey E.;Ding, Tian;Bergmann, Andreas
Hedgehog（Hh）信号通路的失调与包括髓母细胞瘤和基底细胞癌在内的人类癌症的发展相关。小鼠模型中Patched的缺失或Smoothened的激活增加了肿瘤的发生。同样，在果蝇眼睛模型中，Hedgehog信号失调导致眼睛和头部组织过度生长。令人惊讶的是，我们发现，Hh信号失调的细胞不会或只有很少的组织过度生长。相反，它们对细胞凋亡变得更加敏感，并可能最终被消除。然而，这些突变细胞增加了邻近野生型组织中的增殖，即，以非小区自主的方式。这种非细胞自主效应是位置依赖性的，并且仅限于眼睛前部的突变细胞。我们还观察到早熟的非细胞自主分化的遗传马赛克与失调的Hh信号。总之，果蝇眼模型中的这些非细胞自主生长和分化表型揭示了另一种策略，通过该策略，癌基因可以产生支持肿瘤生长的微环境。
Deregulation of the Hedgehog (Hh) signaling pathway is associated with the development of human cancer including medullobastoma and basal cell carcinoma. Loss of Patched or activation of Smoothened in mouse models increases the occurrence of tumors. Likewise, in a Drosophila eye model, deregulated Hedgehog signaling causes overgrowth of eye and head tissues. Surprisingly, we show that cells with deregulated Hh signaling do not or only little contribute to the tissue overgrowth. Instead, they become more sensitive to apoptosis and may eventually be eliminated. Nevertheless, these mutant cells increase proliferation in the adjacent wild-type tissue, i.e., in a non-cell autonomous manner. This non-cell autonomous effect is position-dependent and restricted to mutant cells in the anterior portion of the eye. We also observe precocious non-cell autonomous differentiation in genetic mosaics with deregulated Hh signaling. Together, these non-cell autonomous growth and differentiation phenotypes in the Drosophila eye model reveal another strategy by which oncogenes may generate a supportive micro-environment for tumor growth.
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