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Id2
and Id4 expression and function in glioblastoma multiforme and neural
stem cells Kyuson Yun, Paula Knittle, Akio Mantani, Mark A. Israel
Dartmouth Medial School, Norris Cotton Cancer Center, Hanover, NH,
Hiroshima University, Hiroshima, Japan
Helix-loop-helix (HLH) proteins
regulate proliferation and differentiation in both developing mouse
embryos and in human tumor-derived cell lines.
We found that Id4 and Id2 are
highly expressed in high-grade brain tumor tissues and some brain
tumor-derived cell lines, but only at very low levels in normal mature
brain tissue.
As a prelude to studying the
role of these important genes in the biology of brain tumors, we
examined their function in vivo, analyzing the brains of Id4-/-;
Id2-/-,Id4-/-; and Nestin-Id2 transgenic animals.
Consistent with the known role
of Id genes to inhibit differentiation and promote proliferation, Id4
-/- embryos have smaller brains and this phenotype arises from both
premature differentiation and defective G1-S transition in early
neural stem cells.
Importantly, this phenotype is
more severe in the dorsal medial cortex and hippocampus suggesting
either that other Id genes compensate for Id4 in the lateral cortex or
that in different regions of the brain, there are environmental
influences that can modify the effect of genetic alterations that
regulate brain maturation.
The Id2 single null animal does
not show an obvious brain phenotype, and the Id2/4 double null brain
phenotype is similar to that of the Id4 single null animal, indicating
that Id2 is not compensating for Id4 in the lateral cortex.
Surprisingly, in contrast to in
vitro studies showing that ectopic expression of Id2 inhibits
differentiation and promotes proliferation, ectopic expression of Id2
from the Nestin promoter in neural stem cells leads to a smaller,
rather than a larger, brain phenotype in vivo.
This phenotype results from
both reduced lateral expansion of the neuroepithelium (approximately
30% at E12.5) and increased apoptosis (greater than 10 fold at E12.5),
providing in vivo evidence for the role of Id2 in inducing apoptosis
and implicating Id2 in regulating neural stem cell maintenance,
proliferation, and maturation.
Furthermore, while both mutant
brains show compromised lateral expansion of the neuroepithelium,
there is no increased apoptosis in Id4-/- animals.
Together, the similarities and
differences between Id4-/- and Nestin-Id2 transgenic animals suggest
that Id2 and Id4 affect both overlapping and unique pathways in neural
stem cells.
We are currently testing the
effects of Id2 and Id4 expression in brain tumor derived cell lines by
both gain- and loss-of-function approaches.
In addition, we are examining
the molecular mechanisms underlying the apparently opposing functions
of Id2 and Id4 by identifying downstream target genes of Id4 and
analyzing the pathways that Id4 and its target genes regulate in human
brain tumor-derived cells.
Copyright © 2005 American
Association for Cancer Research. All rights reserved.
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