Premium
Neurofibromatosis 1 (NF1) heterozygosity results in a cell‐autonomous growth advantage for astrocytes
Author(s) -
Bajenaru Michaela Livia,
Donahoe Jessica,
Corral Teresa,
Reilly Karlyne M.,
Brophy Sean,
Pellicer Angel,
Gutmann David H.
Publication year - 2001
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/1098-1136(20010315)33:4<314::aid-glia1030>3.0.co;2-q
Subject(s) - astrocyte , biology , neurofibromatosis , loss of heterozygosity , in vivo , cell growth , neurofibromin 1 , cancer research , heterozygote advantage , in vitro , neuroglia , microbiology and biotechnology , mutation , gene , neuroscience , genetics , central nervous system , allele
Individuals with neurofibromatosis 1 (NF1) develop low‐grade astrocytomas at an increased frequency. To gain insight into the function of the Nf1 gene product as a growth regulator for astrocytes, we examined mice heterozygous for a targeted Nf1 mutation. In our previous studies, we demonstrated increased numbers of proliferating astrocytes in Nf1 heterozygote ( Nf1 +/− ) mice in vivo. We now show that cultured Nf1 +/− astrocytes exhibit a cell‐autonomous growth advantage in vitro associated with increased p21‐ras pathway activation. Furthermore, we demonstrate that Nf1 +/− ;wild‐type N‐ras mice have a similar astrocyte growth advantage in vitro and in vivo as either oncogenic N‐ras or Nf1 +/− ;oncogenic N‐ras mice. Lastly, mice heterozygous for targeted defects in both Nf1 and p53 as well as Nf1 and Rb exhibit 3‐ and 2.5‐fold increases in astrocyte proliferation in vivo, respectively, suggesting that abnormalities in Nf1 ‐ and p53/Rb ‐regulated pathways cooperate in the heterozygous state to confer a growth advantage for brain astrocytes. Collectively, these results provide evidence for a cell‐autonomous growth advantage in Nf1 +/− astrocytes and suggest that some of the brain pathology in individuals with NF1 might result from reduced, but not absent, NF1 gene function. GLIA 33:314–323, 2001. © 2001 Wiley‐Liss, Inc.