title: Hedgehog regulates cerebellar progenitor cell and medulloblastoma apoptosis.
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 therapeutic effect of Hedgehog antagonists during medulloblastoma therapy. Results are discussed in terms of their implications for both cerebellar development and medulloblastoma treatment.
authors: Washington University in St. Louis, Department of Psychiatry, 660 South Euclid, St. Louis, MO 63110, USA. Electronic address: noguchik@psychiatry.wustl.edu.
authors: Kevin Kiyoshi
authors: KK
authors: Noguchi
authors: University of Missouri-St. Louis, Department of Psychological Sciences, One University Boulevard, 325 Stadler Hall, St. Louis, MO 63121, USA. Electronic address: ohcm97@umsl.edu.
authors: Omar Hoseá
authors: OH
authors: Cabrera
authors: Washington University in St. Louis, Department of Psychiatry, 660 South Euclid, St. Louis, MO 63110, USA. Electronic address: swineyb@psychiatry.wustl.edu.
authors: Brant S
authors: BS
authors: Swiney
authors: Washington University in St. Louis, Department of Psychiatry, 660 South Euclid, St. Louis, MO 63110, USA. Electronic address: psc000193@gmail.com.
authors: Patricia
authors: P
authors: Salinas-Contreras
authors: Washington University in St. Louis, Department of Psychiatry, 660 South Euclid, St. Louis, MO 63110, USA. Electronic address: juliek.smith85@gmail.com.
authors: Julie Kathryn
authors: JK
authors: Smith
authors: Washington University in St. Louis, Department of Psychiatry, 660 South Euclid, St. Louis, MO 63110, USA. Electronic address: farbern@psychiatry.wustl.edu.
authors: Nuri B
authors: NB
authors: Farber
mesh_terms: D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D002531:Cerebellum / Q000254:growth & development* / Q000378:metabolism*; D005446:Fluocinolone Acetonide / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000378:metabolism; D016158:Genes, p53; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D008527:Medulloblastoma / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D058953:Neural Stem Cells / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D053823:Hedgehog Proteins; C465570:Shh protein, mouse; D005446:Fluocinolone Acetonide; C035394:fluocinolone; D053148:Caspase 3
keywords: Apoptosis; Cerebellum; External granule layer; Medulloblastoma; Neural progenitor cell; Sonic Hedgehog