MYC expression promotes the proliferation of neural progenitor cells in culture and in vivo.
Primitive neuroectodermal tumors (PNETs) are pediatric brain tumors that result from defects in signaling molecules governing the growth and differentiation of neural progenitor cells. We used the RCAS-TVA system to study the growth effects of three genetic alterations implicated in human PNETs on a subset of neural progenitor cells that express the intermediate filament protein, nestin. The genetic alterations tested were: 1) overexpression of the cellular oncoprotein, MYC; 2) activation of transcription factor, beta-catenin; and 3) haploinsufficiency of Ptc, the hedgehog receptor gene. The RCAS-TVA system uses an avian retroviral vector, RCAS, to target gene expression to specific cell types in transgenic mice. To express exogenous genes in neural progenitor cells, we used Ntv-a mice. In these mice, the Nestin gene promoter drives expression of TVA, the cell surface receptor for the virus. Ectopic expression of MYC, but not activated beta-catenin, promoted the proliferation of neural progenitor cells in culture and in the cerebral leptomeninges in vivo. These effects were equally penetrant in mice with Ptc+/- and Ptc+/+ genetic backgrounds. Although overexpression of MYC is not sufficient to cause intraparenchymal tumors, it may facilitate PNET formation by sustaining the growth of undifferentiated progenitor cells.
Fults
Dan
D
Department of Neurosurgery, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City 84132-2303, USA. danfults@hotmail.com
Pedone
Carolyn
C
Dai
Chengkai
C
Holland
Eric C
EC
D000818:Animals; D001921:Brain / Q000378:metabolism; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D005822:Genetic Vectors; D007124:Immunoenzyme Techniques; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018242:Neuroectodermal Tumors, Primitive / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009474:Neurons / Q000378:metabolism; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface; D013234:Stem Cells / Q000378:metabolism; D015534:Trans-Activators; D014162:Transfection; D051176:beta Catenin
C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D016271:Proto-Oncogene Proteins c-myc; C000606240:Ptch1 protein, mouse; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D015534:Trans-Activators; D051176:beta Catenin