Inactivation of NF1 in CNS causes increased glial progenitor proliferation and optic glioma formation.
The gene responsible for neurofibromatosis type 1 (NF1) encodes a tumor suppressor that functions as a negative regulator of the Ras proto-oncogene. Individuals with germline mutations in NF1 are predisposed to the development of benign and malignant tumors of the peripheral and central nervous system (CNS). Children with this disease suffer a high incidence of optic gliomas, a benign but potentially debilitating tumor of the optic nerve; and an increased incidence of malignant astrocytoma, reactive astrogliosis and intellectual deficits. In the present study, we have sought insight into the molecular and cellular basis of NF1-associated CNS pathologies. We show that mice genetically engineered to lack NF1 in CNS exhibit a variety of defects in glial cells. Primary among these is a developmental defect resulting in global reactive astrogliosis in the adult brain and increased proliferation of glial progenitor cells leading to enlarged optic nerves. As a consequence, all of the mutant optic nerves develop hyperplastic lesions, some of which progress to optic pathway gliomas. These data point to hyperproliferative glial progenitors as the source of the optic tumors and provide a genetic model for NF1-associated astrogliosis and optic glioma.
Zhu
Yuan
Y
Center for Developmental Biology and Kent Waldrep Foundation Center for Basic Research on Nerve Growth and Regeneration, University of Texas Southwestern Medical Center, Dallas, TX 75390-9133, USA. yuanzhu@umich.edu
Harada
Takayuki
T
Liu
Li
L
Lush
Mark E
ME
Guignard
Frantz
F
Harada
Chikako
C
Burns
Dennis K
DK
Bajenaru
M Livia
ML
Gutmann
David H
DH
Parada
Luis F
LF
D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D006965:Hyperplasia; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D025542:Neurofibromin 1 / Q000235:genetics / Q000502:physiology*; D009457:Neuroglia / Q000378:metabolism* / Q000473:pathology; D009900:Optic Nerve / Q000473:pathology; D020339:Optic Nerve Glioma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013234:Stem Cells / Q000502:physiology*
D025542:Neurofibromin 1