Disease relevance of Nf1

• Using tissue-specific gene inactivation, we show that endothelial-specific inactivation of Nf1 recapitulates key aspects of the complete null phenotype, including multiple cardiovascular abnormalities involving the endocardial cushions and myocardium [1].
• Unlike humans, mice that are heterozygous for a mutation in Nf1 do not develop neurofibromas [2].
• Some heterozygous Nf1 mutant mice develop a similar myeloproliferative disorder (MPD), and adoptive transfer of Nf1-deficient fetal liver cells consistently induces this MPD [3].
• In contrast, here we present data that mice mutant for Trp53 and Nf1 on a 129S4/SvJae background are highly resistant to developing astrocytoma [4].
• We have shown previously that mice mutant for Trp53 and Nf1 develop astrocytoma, progressing to glioblastoma, on a C57BL/6J strain background [4].
• Nf1 has an important role in the development of joints, as shown by fusion of the hip joints and other joint abnormalities, which are not observed in neurofibromatosis type I. Thus, neurofibromin has multiple essential roles in skeletal development and growth [5].
• Inhibiting microglia activation in genetically engineered Nf1 mice significantly reduces mouse optic glioma proliferation in vivo [6].
• We suggest that timing of Nf1 mutation is critical for neurofibroma formation [7].
• Adult P0a-Cre+Nf1(fl/-) mice developed neurofibromas, and Nf1(+/-)Ink4a/Arf(-/-) and Nf1/p53(+/-) mice developed MPNSTs, but NCSCs did not persist postnatally in affected locations in these mice [8].

Psychiatry related information on Nf1

• Importantly, NF1 causes learning disabilities and attention deficits [9].
• A previous study showed that the learning and memory deficits of a mouse model of NF1 (nf1+/-) appear to be caused by excessive p21Ras activity leading to impairments in long-term potentiation (LTP), a cellular mechanism of learning and memory [9].
• The characteristics of NF1, which include cafe-au-lait spots, neurofibromas, Lisch nodules, optic glioma, osseous lesions, macrocephaly, short stature and mental retardation suggest that the genetic lesion affects the proper development of multiple organ systems [10].
• A broad range of both nonverbal and verbal learning disabilities are evident in approximately 30% to 65% of children with NF1 [11].
• Impaired local protein translation at postsynaptic sites has been hypothesized to be the cause of several neurological disorders such as fragile X syndrome, neurofibromatosis-1, Rett syndrome, and other syndromic and non-specific forms of mental retardation [12].

High impact information on Nf1

• These results establish a new and essential role for Nf1 in endothelial cells and confirm the requirement for neurofibromin in the neural crest [1].
• Neurofibromatosis type 2 is an autosomal dominant disorder characterized by tumors, predominantly schwannomas, in the nervous system [13].
• Our findings have implications for the development of a treatment for the learning disabilities associated with NF1 and indicate that the GAP domain of NF1 modulates learning and memory [14].
• Humans with mutations in NF1 develop neurofibromatosis type I (NF1) and have increased risk of optic gliomas, astrocytomas and glioblastomas [15].
• As in humans, the learning and memory deficits of the Nf1+/- mice are restricted to specific types of learning, they are not fully penetrant, they can be compensated for with extended training, and they do not involve deficits in simple associative learning [16].

Chemical compound and disease context of Nf1

• The NF2 protein, called schwannomin or merlin, is inactivated in virtually all schwannomas and meningiomas [17].
• In light of our previous finding that aberrant expression of the MET receptor tyrosine kinase contributes to the invasiveness of human NF1-associated malignant peripheral nerve sheath tumors, we sought to determine whether MET expression is aberrant in the brains of Nf1 mutant mice [18].
• We have investigated farnesyltransferase inhibitor (FTI) L-744,832 in an in vivo murine model of myeloid leukemia that is associated with inactivation of the Nf1 tumor suppressor gene [19].
• Furthermore, high-dose DHA reversed the stimulation of MPNST cell growth by a number of growth factors suggested to have a pathogenic effect in NF1 and inhibited MPNST growth in vivo [20].
• These studies suggest that the learning disabilities associated with neurofibromatosis 1 are caused by excessive Ras activity that leads to increased gamma-aminobutyric acid (GABA(A)) inhibition and to decreased long-term potentiation [21].

Biological context of Nf1

• We also show that the Nf1(+/-) mice have increased GABA (gamma-amino butyric acid)-mediated inhibition and specific deficits in long-term potentiation, both of which can be reversed by decreasing Ras function [22].
• Genetic and biochemical evidence that haploinsufficiency of the Nf1 tumor suppressor gene modulates melanocyte and mast cell fates in vivo [23].
• Neurofibromas occur with high penetrance in mice in which Nf1 is ablated in Schwann cells in the context of a heterozygous mutant (Nf1+/-) microenvironment [24].
• Susceptibility to astrocytoma in mice mutant for Nf1 and Trp53 is linked to chromosome 11 and subject to epigenetic effects [4].
• Finally, we demonstrate that mast cells from both Fas antigen-deficient mice and Nf1 +/- mice are resistant to apoptosis following kit-L withdrawal in vivo [25].

Anatomical context of Nf1

• Nf1 has an essential role in endothelial cells [1].
• Deficiency in neurofibromin (encoded by Nf1) in mice results in mid-embryonic lethality owing to cardiac abnormalities previously thought to be secondary to cardiac neural-crest defects [1].
• Here, we show that haploinsufficiency at Nf1 perturbs cell fates in mast cells in vivo, and partially rescues coat color and mast cell defects in W(41) mice [23].
• Somatic inactivation of murine Nf1 in Schwann cells is necessary, but not sufficient, to initiate neurofibroma formation [24].
• Additionally, we find decreased Nf1 expression in bone marrow-derived myeloid cells from ICSBP-/- mice [26].

Associations of Nf1 with chemical compounds

• Recently neurofibromin, the protein encoded by NF1, was shown to negatively regulate Ras activity in Nf1-/- murine myeloid hematopoietic cells in vitro through the c-kit receptor tyrosine kinase (dominant white spotting, W) [23].
• Therefore, these results demonstrate that lovastatin may prove useful in the treatment of Neurofibromatosis Type 1 [9].
• Cyclophosphamide exposure cooperated strongly with heterozygous inactivation of Nf1 in myeloid leukemogenesis, while etoposide did not [27].
• Ex vivo, Nf1 heterozygosity was associated with increased inducible osteoclasts in PTH-treated bone marrow cells and impairment of the actin stress fiber and cyclic adenosine monophosphate response to PTH in osteoprogenitors [28].
• The NF2 protein merlin belongs to the band 4.1 family of proteins that link membrane proteins to the cytoskeleton and are thought to be involved in dynamic cytoskeletal reorganization [29].

Physical interactions of Nf1

• A novel isoform of beta-spectrin II localizes to cerebellar Purkinje-cell bodies and interacts with neurofibromatosis type 2 gene product schwannomin [30].

Regulatory relationships of Nf1

• Human JMML and murine Nf1-deficient cells are hypersensitive to granulocyte-macrophage colony-stimulating factor (GM-CSF) in methylcellulose cultures [3].
• Role of TC21/R-Ras2 in enhanced migration of neurofibromin-deficient Schwann cells [31].
• Nf1 mutant progenitors also abnormally coexpress the glial differentiation markers O4 and GFAP [32].
• The NF1 tumor suppressor gene encodes a GTPase-activating protein called neurofibromin that negatively regulates Ras signaling [24].
• Presently, how NF2 is expressed during embryonic development and in the tissues affected by neurofibromatosis type 2 (NF2) has not been well defined [33].

Other interactions of Nf1

• Nf1 and Gmcsf interact in myeloid leukemogenesis [3].
• Hyperactivation of p21(ras) and the hematopoietic-specific Rho GTPase, Rac2, cooperate to alter the proliferation of neurofibromin-deficient mast cells in vivo and in vitro [34].
• In contrast, we found a low incidence of neural tube defects in heterozygous Splotch mice that also harbored a mutation in one Nf1 allele [35].
• Remarkably, U0126, an inhibitor of ERK activation, at doses which reduced the hyperactive pERK levels in NF1(+/-) mice to the levels observed in control mice, caused a reduction in the deficits in early-phase LTP and completely rescued the long-term LTP deficits [36].
• We report that in contrast to the narrow spectrum of benign tumors in human NF2 patients, Nf2 heterozygous mice develop a variety of malignant tumors [37].

Analytical, diagnostic and therapeutic context of Nf1

• To study the function of NF1 in normal development and to try and develop a mouse model of NF1 disease, we have used gene targeting in ES cells to generate mice carrying a null mutation at the mouse Nf1 locus [38].
• Importantly, Nf1-/- spinal cord-derived oligodendrocyte progenitors, which are amplified 12-fold, retain the ability to form oligodendrocytes after in vivo transplantation [32].
• However, FK228 is still in clinical trials (phase 2) for a variety of cancers (but not for NF as yet), and not available for most cancer/NF patients [39].
• Recent clinical data suggest that NF1 might be also associated with an increased risk of t-AML after treatment with alkyating agents [27].
• Immunocytochemistry on sections of cortex and cerebellum of unaffected and NF1 individuals and wild-type and NF1-deficient mice showed that the distribution of neurofibromin was similar to that reported for rat [40].

References