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. Author manuscript; available in PMC: 2013 May 1.
Published in final edited form as: Brain Res Bull. 2011 Aug 10;88(1):58–71. doi: 10.1016/j.brainresbull.2011.08.005

Table 1.

Genetically Engineered Mouse Models of PNS Neoplasia

Transgenic
Mouse Model		 Phenotype Limitations
Early Models Nf1Δ31/Δ31 die by E13.5 due to cardiac
failure		 early death prevents observation of
tumorigenic effects of Nf1 loss
Nf1Δ31/+ develop pheochromocytomas
(15% incidence); show
accelerated development of
other non-NF1 tumors as
compared to wild-type mice		 no neurofibromas or MPNSTs
observed
Nf1−/−;Nf1+/−
chimeras		 multiple plexiform
neurofibromas present in
animals with intermediate level
of chimerism		 cannot control which cell types are
Nf1+/− and which are Nf1−/−
Nf1flox/flox;Krox20
-Cre 		Schwann cell hyperplasia no neurofibromas or MPNSTs
observed
Nf1flox/−;Krox20
-Cre 		plexiform neurofibroma
development by 1yr of age
(demonstrating importance of
both Nf1+/− and Nf1−/− cells in
neurofibroma formation)		 Krox20 promoter is expressed in
Schwann cells and boundary cap
cells, making it hard to identify a
clear progenitor
Tumor Microenvironment Models Nf1flox/flox; Krox2-
Cre
transplanted
with Nf1+/− bone
marrow		 developed plexiform
neurofibromas infiltrated by
donor mast cells
(demonstrating importance of
Nf1 haploinsufficiency in
hematopoeitic lineage for
neurofibroma formation)		 Other Nf1+/− cell types within the
hematopoietic lineage may
contribute to neurofibroma
development
Nf1flox/flox; Krox2-
Cre
transplanted
with Nf1+/−;c-
KitW41/W41 bone
marrow		 no neurofibromas developed
(demonstrating importance of
c-Kit signaling in Nf1
haploinsufficient cells in the
hematopoeitic lineage)
Nf1flox/+; Krox2-
Cre
transplanted
with Nf1+/+ bone
marrow		 no neurofibromas developed
(demonstrating importance of
Nf1 haploinsufficiency in
hematopoeitic lineage for
neurofibroma formation)
Tumor Cell of Origin Models Nf1 ablation in
Migrating Neural
Crest 		Nf1flox/−; Wnt1-
Cre, 		died at birth; no neurofibromas
developed		 early death prevents observation of
tumorigenic effects of Nf1 loss
Nf1flox/-; Mpz-Cre
Nf1flox/−; Pax3-
Cre
ablation in
Schwann
Cell 		Nf1flox/−; 3.9Periostin-Cre died by 4 weeks after birth; no
neurofibroma development
observed		 early death prevents observation of
tumorigenic effects of Nf1 loss
Nf1flox/−; P0a-Cre plexiform neurofibroma
formation observed by 15-20
months		 due to broad P0a promoter
expression in the Schwann cell
lineage, a definitive cell of origin still
could not be identified
Nf1flox/flox; Dhh-
Cre 		plexiform and subcutaneous
neurofibroma development
(demonstrating that an Nf1+/−
microenvironment might not be
strictly required for
neurofibroma formation)		 Dhh promoter expression in
progenitor cells capable of
differentiation into both Schwann
cells and endoneurial fibroblasts
Nf1 ablation
in SKPs 		Nf1flox/−; CMV-
CreERT2;
Rosa26 		dermal neurofibromas
generated ~6 months following
topical tamoxifen
administration		 likely that ablation of Nf1 in non-SKP
cells in dermis contributes to
neurofibroma formation
MPNST Formation Driven by
Dual Tumor Suppressor Loss 		trans-linked
Nf1+/−;p53+/− 		developed non-MPNST
sarcomas characteristic of p53
LOH		 no MPNST formation
cis-linked Nf1+/−
;p53+/− 		developed MPNSTs (~30%
incidence)		 no neurofibroma precursor lesion
Nf1+/−p16Ink4a−/− accelerated development of
tumors characteristic of
p16INK4a loss		 no MPNST formation
Nf1+/−p19Arf−/− accelerated development of
tumors characteristic of p19Arf
loss		 no MPNST formation
Nf1+/−
p16Ink4a/p19Arf−/− 		developed MPNSTs (~30%
incidence)		 no neurofibroma precursor lesion
PNS Tumor Formation
Driven by Ras Activation 		LSLNrasG12V/+;
CAMK2-Cre 		pigmentary abnormalities of
skin and dermal neurofibromas
observed		 expression of the CAMK2 promoter
in the Schwann cell lineage has not
been clearly defined
LSLKras2BG12D/+;
mGFAP-Cre 		no obvious phenotype no neurofibromas observed
LSLKras2BG12D/+
Ptenflox/+;
mGFAP-Cre 		plexiform neurofibroma
development by 4 months of
age with progression to
MPNSTs by 7 months		 unclear how necessary Pten loss of
function is to neurofibroma formation
in the context of Nf1 loss
PNS Tumor Formation
Driven by Dysregulated
Growth Factor Signaling 		P0-GGF β 3 neurofibroma formation with
progression to MPNSTs by 6-
10 months		 not yet clear whether and how
dysregulated NRG1 signaling
interacts with neurofibromin loss
CNPase-EGFR Schwann cell hyperplasia with
mast cell recruitment and
fibrosis		 neurofibroma formation exceedingly
rare at very advanced age; no
MPNSTs observed