Hedgehog regulates cerebellar progenitor cell and medulloblastoma apoptosis

Neurobiology of Disease
Kevin K NoguchiNuri B Farber

Abstract

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 ther...Continue Reading

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Citations

Apr 4, 2016·Journal of Experimental & Clinical Cancer Research : CR·Zhai ErtaoCai Shirong
Jan 19, 2019·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Farasat ZamanLars Sävendahl
May 5, 2018·Cell Death & Disease·Bin WangMiao Sun
Jul 20, 2020·The Journal of Investigative Dermatology·Iain S HaslamZhiCao Yue

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