Noguchi Kevin Kiyoshi, Cabrera Omar Hoseá, Swiney Brant S, Salinas-Contreras Patricia, Smith Julie Kathryn, Farber Nuri B
Washington University in St. Louis, Department of Psychiatry, 660 South Euclid, St. Louis, MO 63110, USA.
University of Missouri-St. Louis, Department of Psychological Sciences, One University Boulevard, 325 Stadler Hall, St. Louis, MO 63121, USA.
Neurobiol Dis. 2015 Nov;83:35-43. doi: 10.1016/j.nbd.2015.08.020. Epub 2015 Aug 28.
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 that 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 that 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.
外颗粒层（EGL）是一个增殖区域，它产生小脑90%以上的神经元，但也可能恶性转化为一种名为髓母细胞瘤的小脑肿瘤（儿童中最常见的恶性脑肿瘤）。目前的观点认为，刺猬信号通路（Hedgehog）的激活是EGL神经祖细胞（NPCs）和髓母细胞瘤的一种强大增殖信号。然而，Hedgehog信号通路在神经管中也作为一种存活信号，通过控制NPC凋亡来调节背腹模式形成。在这里，我们表明，Hedgehog信号的激活在EGL和髓母细胞瘤中也是一种强大的存活信号，在小鼠信号缺失后的数小时内会产生大量的凋亡反应。这种毒性可由多种Hedgehog拮抗剂（维莫德吉、环杷明和杰尔文）产生，且依赖于Bax/Bak，但不依赖于p53。最后，由于糖皮质激素也能诱导EGL和髓母细胞瘤凋亡，我们表明Hedgehog对凋亡的影响可以独立于糖皮质激素刺激而发生。这种作用可能在小脑发育中起主要作用，通过引导EGL增殖发生的位置，从而在形态上塑造生长。它也可能是Hedgehog拮抗剂在髓母细胞瘤治疗中一种以前未知的主要治疗作用。我们将根据这些结果对小脑发育和髓母细胞瘤治疗的影响进行讨论。
