Hedgehog regulates cerebellar progenitor cell and medulloblastoma apoptosis.
Hedgehog regulates cerebellar progenitor cell and medulloblastoma apoptosis.
复制标题
DOI：
10.1016/j.nbd.2015.08.020
复制
发表时间：
2015-11
影响因子：
6.1
通讯作者：
Farber NB
中科院分区：
文献类型：
--
作者：
Noguchi KK;Cabrera OH;Swiney BS;Salinas-Contreras P;Smith JK;Farber NB
外颗粒层 (EGL) 是一个增殖区域，产生小脑中 90% 以上的神经元，但也可以恶性转化为称为髓母细胞瘤（儿童最常见的恶性脑肿瘤）的小脑肿瘤。目前的教条认为 Hedgehog 刺激是 EGL 神经祖细胞 (NPC) 和髓母细胞瘤的有效增殖信号。然而，Hedgehog 通路也在神经管中充当生存信号，通过控制 NPC 凋亡来调节背腹模式。在这里，我们发现 Hedgehog 刺激也是 EGL 和髓母细胞瘤中有效的生存信号，在小鼠信号丢失的数小时内产生大量的细胞凋亡反应。这种毒性可由多种 Hedgehog 拮抗剂（vismodegib、cyclopamine 和 jervine）产生，并且依赖于 Bax/Bak，但不依赖于 p53。最后，由于糖皮质激素还可以诱导 EGL 和髓母细胞瘤细胞凋亡，因此我们表明 Hedgehog 对细胞凋亡的影响可以独立于糖皮质激素刺激而发生。这种效应可能通过指导 EGL 增殖发生的位置从而在形态上塑造生长而在小脑发育中发挥重要作用。这也可能是Hedgehog拮抗剂在髓母细胞瘤治疗过程中以前未知的主要治疗作用。讨论了结果对小脑发育和髓母细胞瘤治疗的影响。
The external granule layer (EGL) is a proliferative region that produces over 90% of the neurons in the cerebellum but can also malignantly transform into a cerebellar tumor called the medulloblastoma (the most common malignant brain tumor in children). Current dogma considers Hedgehog stimulation a potent proliferative signal for EGL neural progenitor cells (NPCs) and medulloblastomas. However, the Hedgehog pathway also acts as a survival signal in the neural tube where it regulates dorsoventral patterning by controlling NPC apoptosis. Here we show Hedgehog stimulation is also a potent survival signal in the EGL and medulloblastomas that produces a massive apoptotic response within hours of signal loss in mice. This toxicity can be produced by numerous Hedgehog antagonists (vismodegib, cyclopamine, and jervine) and is Bax/Bak dependent but p53 independent. Finally, since glucocorticoids can also induce EGL and medulloblastoma apoptosis, we show Hedgehog's effects on apoptosis can occur independent of glucocorticoid stimulation. This effect may play a major role in cerebellar development by directing where EGL proliferation occurs thereby morphologically sculpting growth. It may also be a previously unknown major therapeutic effect of Hedgehog antagonists during medulloblastoma therapy. Results are discussed in terms of their implications for both cerebellar development and medulloblastoma treatment.