Neurofibromatosis 1 Gene Research Articles

Intraoral presentation of multiple malignant peripheral nerve sheath tumors associated with neurofibromatosis-1

Neurofibromatosis-1 (NF-1) is a relatively common autosomal dominant disease characterized by multiple cutaneous fibromatoses and café au lait spots. It is associated with the mutation of NF-1 gene, a tumor suppressor gene located on chromosome 17q11.2. Hence, it can be considered as a familial cancer predisposition syndrome in which the affected individuals are at increased risk of developing malignancies. Intraoral neurofibromas associated with NF-1 are quite common, but the occurrence of malignant peripheral nerve sheath tumor (MPNST) in the oral cavity is very rare. Oral MPNST can occur either de novo or by malignant transformation of neurofibromas or very rarely can represent a metastatic lesion. Here, we present a case of MPNST involving the maxillary region, in a patient with NF-1. Since MPNST often creates a diagnostic dilemma, histopathologic criteria for the diagnosis of MPNST are also discussed.

Long-range DNA interactions are specifically altered by locked nucleic acid-targeting of a CTCF binding site

Long-range DNA interactions play an important role in gene expression. CCCTC-binding factor (CTCF), a ubiquitously expressed and evolutionarily conserved 11-zinc-finger DNA binding protein, is intimately involved in gene regulation, helping to establish and maintain chromatin architecture and long-range DNA interactions. In order to study the effects of manipulating long range chromatin interactions in the regulation of the neurofibromatosis gene NF1, we targeted Zorro locked nucleic acids (Zorro LNA) to a single CTCF binding site at an NF1 locus in human fibroblast cells. Using chromatin immunoprecipitation, we determined that this Zorro LNA altered CTCF and RNA polymerase II binding at three separate and distinct regions in the NF1 gene. This change in protein binding was associated with changes in long-range DNA interactions at the NF1 locus and downregulation of NF1 gene expression. This study describes an efficient and convenient method to manipulate chromatin structure and alter gene expression that is regulated by long-range DNA interactions without changing the DNA sequence. The use of specific Zorro LNA probes may facilitate our efforts to understand the interactions between chromatin architecture and gene expression.

Epidemiology and etiology of meningioma

Although most meningiomas are encapsulated and benign tumors with limited numbers of genetic aberrations, their intracranial location often leads to serious and potentially lethal consequences. They are the most frequently diagnosed primary brain tumor accounting for 33.8% of all primary brain and central nervous system tumors reported in the United States between 2002 and 2006. Inherited susceptibility to meningioma is suggested both by family history and candidate gene studies in DNA repair genes. People with certain mutations in the neurofibromatosis gene (NF2) have a very substantial increased risk for meningioma. High dose ionizing radiation exposure is an established risk factor for meningioma, and lower doses may also increase risk, but which types and doses are controversial or understudied. Because women are twice as likely as men to develop meningiomas and these tumors harbor hormone receptors, an etiologic role for hormones (both endogenous and exogenous) has been hypothesized. The extent to which immunologic factors influence meningioma etiology has been largely unexplored. Growing emphasis on brain tumor research coupled with the advent of new genetic and molecular epidemiologic tools in genetic and molecular epidemiology promise hope for advancing knowledge about the causes of intra-cranial meningioma. In this review, we highlight current knowledge about meningioma epidemiology and etiology and suggest future research directions.

The advanced genomics research of neurofibromatosis type 1

Neurofibromatosis type 1 is a term of Von Recklinghausenan.It is an autosomal dominant inherited disease which derived by neural crest cell.Prevalence of this disease is 1/3000 1/3500 and is a disease with the highest mutation rate.The pathogenesis of neurofibromatosis type 1 is associated with the deficiency of NF1 gene.Recently,the genetics and genomics research of neurofibromatosis make a great progress.With the development of gene linkage and position cloning technology,the gene sequence of neurofibromatosis type 1 has been found.Recent research of genetics and genomics of NF1 and the structure and function,abnormal expression,the relation of genotype and phenotype,the mutation sensitivity domain of NF1 gene were reviewed. Key words: neurofibromatosis type 1; neurofibromatosis gene; genetics; genomics; gene mutation

Further genotype – phenotype correlations in neurofibromatosis 2

Neurofibromatosis 2 (NF2) is caused by mutations in the NF2 gene predisposing carriers to develop nervous system tumours. Different NF2 mutations result in either loss/reduced protein function or gain of protein function (abnormally behaving mutant allele i.e. truncated protein potentially causing dominant negative effect). We present a comparison between the clinical presentations of patients with mutations that are predicted to produce truncated protein (nonsense/frameshift mutations) to those that results in loss of protein expression (large deletions) to elucidate further genotype-phenotype correlations in NF2. Patients with nonsense/frameshift mutations have a younger age of diagnosis and a higher prevalence/proportion of meningiomas (p = 0.002, p = 0.014), spinal tumours (p = 0.004, p = 0.004) and non-VIII cranial nerve tumours (p = 0.006, p = 0.003). We also found younger age of diagnosis of vestibular schwannomas (p = 0.007), higher mean numbers of cutaneous lesions (p = 0.003) and spinal tumours (p = 0.006) in these patients. With respect to NF2 symptoms, we found younger age of onset of hearing loss (p = 0.010), tinnitus (p = 0.002), paraesthesiae (p = 0.073), wasting and weakness (p = 0.001) and headaches (p = 0.049) in patients with nonsense/frameshift mutations. Our comparison shows, additional, new correlations between mutations in the NF2 gene and the NF2 disease phenotype, and this further confirms that nonsense/frameshift mutations are associated with more severe NF2 symptoms. Therefore patients with this class of NF2 mutation should be followed up closely.

Further genotype–phenotype correlations in neurofibromatosis 2

Selvanathan SK, Shenton A, Ferner R, Wallace AJ, Huson SM, Ramsden RT, Evans DG. Further genotype–phenotype correlations in neurofibromatosis 2. Neurofibromatosis 2 (NF2) is caused by mutations in the NF2 gene predisposing carriers to develop nervous system tumours. Different NF2 mutations result in either loss/reduced protein function or gain of protein function (abnormally behaving mutant allele i.e. truncated protein potentially causing dominant negative effect). We present a comparison between the clinical presentations of patients with mutations that are predicted to produce truncated protein (nonsense/frameshift mutations) to those that results in loss of protein expression (large deletions) to elucidate further genotype–phenotype correlations in NF2. Patients with nonsense/frameshift mutations have a younger age of diagnosis and a higher prevalence/proportion of meningiomas (p = 0.002, p = 0.014), spinal tumours (p = 0.004, p = 0.004) and non-VIII cranial nerve tumours (p = 0.006, p = 0.003). We also found younger age of diagnosis of vestibular schwannomas (p = 0.007), higher mean numbers of cutaneous lesions (p = 0.003) and spinal tumours (p = 0.006) in these patients. With respect to NF2 symptoms, we found younger age of onset of hearing loss (p = 0.010), tinnitus (p = 0.002), paraesthesiae (p = 0.073), wasting and weakness (p = 0.001) and headaches (p = 0.049) in patients with nonsense/frameshift mutations. Our comparison shows, additional, new correlations between mutations in the NF2 gene and the NF2 disease phenotype, and this further confirms that nonsense/frameshift mutations are associated with more severe NF2 symptoms. Therefore patients with this class of NF2 mutation should be followed up closely.

Nf1 deficiency cooperates with oncogenic K-RAS to induce acute myeloid leukemia in mice

AbstractHyperactive RAS signaling is caused by mutations in RAS genes or a deficiency of the neurofibromatosis gene (NF1) and is common in myeloid malignancies. In mice, expression of oncogenic K-RAS or inactivation of Nf1 in hematopoietic cells results in myeloproliferative disorders (MPDs) that do not progress to acute myeloid leukemia (AML). Because NF1 is a RAS-GTPase–activating protein it has been proposed that NF1 deficiency is functionally equivalent to an oncogenic RAS. It is not clear, however, whether Nf1 deficiency would be redundant in K-RAS–induced MPD development or whether the 2 mutations would cooperate in leukemogenesis. Here, we show that the simultaneous inactivation of Nf1 and expression of K-RASG12D in mouse hematopoietic cells results in AML that was fatal in primary mice within 4 weeks and transplantable to sublethally irradiated secondary recipients. The data point to a strong cooperation between Nf1 deficiency and oncogenic K-RAS.

Juvenile xanthogranuloma in a child with previously unsuspected neurofibromatosis type 1 and juvenile myelomonocytic leukemia

The association of neurofibromatosis 1 (NF1), juvenile xanthogranulomas (JXG), and juvenile myelomonocytic leukemia (JMML) has been previously reported. We describe herein this triad in a Caucasian male infant with a pathogenic mutation in the NF1 gene (neurofibromin). The clinical course from initial presentation to final diagnosis is detailed; the physical features and hematologic characteristics are discussed. The patient underwent bone marrow transplantation and is currently in remission. Children with concurrent cutaneous café-au-lait and JXG lesions should be evaluated and monitored closely for the possible development of JMML.

GASTRIC SCHWANNOMA WITH ADJACENT EXTERNAL PROGRESSION HARBORED ABERRANT NF2 GENE

Gastric schwannomas are rare benign mesenchymal tumors. We describe a schwannoma of gastric origin with adjacent external progression. Sections showed a spindle cell tumor arranged in interlaced bundles and fascicles that was S-100 and CD34 positive but c-KIT protein negative. Histology and immunohistochemistry revealed the typical appearance of a gastric schwannoma. Genetic evaluation revealed that the tumor harbored a point mutation in exon 6 of the tumor suppressor neurofibromatosis 2 (NF2) gene, which resulted in an amino acid substitution of NF2 protein, and no mutation in exon 4b of the NF1 gene. In conclusion, we identified a rare mutation of the NF2 gene in gastric schwannoma. A diagnosis can only be definitive when based on histological and immunohistochemical findings. Digestive tract schwannomas are rare mesenchymal tumors that are differentiated from gastrointestinal stromal tumors by the absence of KIT protein. Follow up suggested that complete resection is an effective long-term treatment strategy.

Expression of the Tumor Suppressor Genes NF2, 4.1B, and TSLC1 in Canine Meningiomas

Meningiomas are common primary brain tumors in dogs; however, little is known about the molecular genetic mechanisms involved in their tumorigenesis. Several tumor suppressor genes have been implicated in meningioma pathogenesis in humans, including the neurofibromatosis 2 (NF2), protein 4.1B (4.1 B), and tumor suppressor in lung cancer-1 (TSLC1) genes. We investigated the expression of these tumor suppressor genes in a series of spontaneous canine meningiomas using quantitative real-time reverse transcription polymerase chain reaction (RT-PCR) (NF2; n = 25) and western blotting (NF2/merlin, 4.1B, TSLC1; n = 30). Decreased expression of 4.1B and TSLC1 expression on western blotting was seen in 6/30 (20%) and in 15/30 (50%) tumors, respectively, with 18/30 (60%) of meningiomas having decreased or absent expression of one or both proteins. NF2 gene expression assessed by western blotting and RT-PCR varied considerably between individual tumors. Complete loss of NF2 protein on western blotting was not seen, unlike 4.1B and TSLC1. Incidence of TSLC1 abnormalities was similar to that seen in human meningiomas, while perturbation of NF2 and 4.1B appeared to be less common than reported for human tumors. No association was observed between tumor grade, subtype, or location and tumor suppressor gene expression based on western blot or RT-PCR. These results suggest that loss of these tumor suppressor genes is a frequent occurrence in canine meningiomas and may be an early event in tumorigenesis in some cases. In addition, it is likely that other, as yet unidentified, genes play an important role in canine meningioma formation and growth.

Congenital pseudarthrosis of neurofibromatosis type 1: Impaired osteoblast differentiation and function and altered NF1 gene expression

Three patients with neurofibromatosis 1 (NF1) were operated for congenital pseudarthrosis (PA) of the tibia. Three non-NF1 patients served as reference. Both NF1 mRNA and protein were detected in the PAs and in rows of osteoblasts and numerous osteoclasts next to the NF1-related PA arguing against inactivation of both NF1 alleles in the resident cells. Analyses on mesenchymal stem cells (MSCs) cultured from the red bone marrow of 1) next to PA of the affected NF1 tibiae, 2) the non-affected NF1 iliac crest of the same patients, and from 3) non-NF1 bone marrow demonstrated that the potential to form bone in vitro was the lowest in cells from the affected NF1-tibiae. The latter cells also displayed reduced levels of NF1 mRNA and protein, and upregulated phosphorylated p44/42 MAPK levels, consistent with an upregulated Ras-pathway. An exhaustive NF1 gene analysis detected constitutional mutation in each case, but no second hits or loss of heterozygosity were found. However, one patient displayed a mutation resulting in two potential active splice sites ultimately affecting exon 6. Interestingly, only one of the respective transcripts was detected in cells from the iliac crest, but two novel transcripts were detected in MSCs cultured from site next to PA. This finding may identify a novel mechanism how a single NF1 gene mutation may exert distinct effects on separate anatomical locations. The molecular pathogenesis of NF1-related PA apparently may not be entirely explained by second mutations or loss of heterozygosity of the NF1 gene.

Vestibular Schwannoma Quantitative Polymerase Chain Reaction Expression of Estrogen and Progesterone Receptors

Determine the role of estrogen receptor (ER) and progesterone receptor (PR) expression in sporadic and neurofibromatosis 2 (NF2)-related vestibular schwannomas (VS). Growth and proliferation signaling in human VS tumorigenesis may play a key role in molecular therapeutic targeting. VS carry mutations of the NF2 gene encoding the tumor suppressor, merlin, which interacts with ErbB2 in Schwann cells, implicating ErbB receptors in VS tumorigenesis. ErbB receptor family members are overexpressed or constitutively activated in many human tumors, and are effective therapeutic targets in some human cancers. VS occur more frequently in women and are larger, more vascular, and demonstrate increased growth rates during pregnancy. ER and PR may play a role in ErbB pathway activation and VS progression. Quantitative real-time polymerase chain reaction (qRT-PCR) for ER and PR messenger RNA was performed using greater auricular and vestibular nerve controls (n = 8), sporadic VS (n = 23), and NF2-related VS (n = 16) tissues. The qRT-PCR data were normalized with standardization to a single constitutively expressed control gene, human cyclophylin. Reverse transcription of messenger RNA from control and tumor specimens followed by RT Q-PCR demonstrated differences in ER and PR gene expression between sporadic and NF2-related VS. ER and PR expression in VS might have implications for development of a VS-specific drug delivery system using antihormone and ErbB pathway small molecule inhibitors, due to crosstalk between these receptors. These signals may be critical for re-establishing ErbB-mediated cell density dependent growth inhibition.

Neurofibromatosis 2: finding the gene (A study of teh processes involved in finding a new gene locus using NF2 as a case study)

The Neurofibromatoses are two autosomal dominant disorders classified as Neurofibromatoses type1 (NF1) and Neurofibromatoses type2 (NF2). They are primarily neural tumours with distinct clinical and genetic characteristics even though areas of clinical similarities exist.1 Neurofibromatosis 2 is characterised by bilateral acoustic neuromas and a predisposition to the formation of tumours. The search for the NF2 gene started with observational studies of inheritance patterns in large families expressing the NF2 phenotype, which led to the realisation that NF2 is a genetic disease. The work of various groups of researchers using deletion mapping, somatic cell hybrid maps and radiation hybrid maps with linkage analysis firmly established that the NF2 gene was located in a region located on the long arm of chromosome 22 (22q11.1-q13.1); a region with several markers any of which could have been the candidate gene. With the help of further studies, including chromosomal breakpoint studies and ‘chromosome walking' techniques the NF2 region was further narrowed to a size small enough to allow for cloning of the entire NF2 region and later, sequencing of the NF2 gene. Thus the gene for Neurofibromatosis 2, a disease that was first described about 1930, was eventually discovered in 1993. This article attempts to review the processes that made the discovery of the gene possible.Nigerian Journal of Health and Biomedical Sciences Vol. 7 (1) 2008 pp. 64-71

Molecular Biology of Unreresectable Meningiomas: Implications for New Treatments and Review of the Literature

Even though meningiomas are most often benign tumors, they can be locally invasive and can develop in locations that prevent surgical treatment. The molecular and biologic factors underlying meningioma development are only now beginning to be understood. Genetic factors such as mutations in the neurofibromatosis-2 gene and in chromosomes 1, 9, and 10 play important roles in meningioma development and may be responsible for atypical tumors in some cases. Cellular factors such as telomerase activation and tyrosine kinase receptor mutations may also play an important role. Finally, autocrine and paracrine factors including epidermal growth factor receptor, platelet-derived growth factor-1, and fibroblast growth factor have been implicated in the development of some tumors. Although the relationship between the various factors implicated in tumor development is unknown, understanding these factors will be critical in the treatment of malignant or surgically inaccessible tumors.

Influence of hormones and hormone metabolites on the growth of schwann cells derived from embryonic stem cells and on tumor cell lines expressing variable levels of neurofibromin

Loss of neurofibromin, the protein product of the tumor suppressor gene neurofibromatosis type 1 (NF1), is associated with neurofibromas, composed largely of Schwann cells. The number and size of neurofibromas in NF1 patients have been shown to increase during pregnancy. A mouse embryonic stem cell (mESC) model was used, in which mESCs with varying levels of neurofibromin were differentiated into Schwann-like cells. NF1 cell lines derived from a malignant and a benign human tumor were used to study proliferation in response to hormones. Estrogen and androgen receptors were not expressed or expressed at very low levels in the NF1+/+ cells, at low levels in NF1+/-cells, and robust levels in NF1-/-cells. A 17beta-estradiol (E2) metabolite, 2-methoxy estradiol (2ME2) is cytotoxic to the NF1-/- malignant tumor cell line, and inhibits proliferation in the other cell lines. 2ME2 or its derivatives could provide new treatment avenues for NF1 hormone-sensitive tumors at times of greatest hormonal influence.

Merlin Expression in Secretory Meningiomas: Evidence of an NF2-independent Pathogenesis?

One of the most common chromosomal regions implicated in the meningiomas tumorigenesis is 22q12 where the neurofibromatosis 2 (NF2) gene resides. The NF2 tumor-suppressor gene encodes for the merlin/schwannomin protein, which is responsible for the inherited disease neurofibromatosis 2. NF2 gene mutations predominantly occur in transitional and fibroblastic meningiomas, whereas the meningothelial variant is less affected. Secretory meningioma is an infrequent meningioma subtype. Its most typical morphologic feature is the presence of intracytoplasmic or extracytoplasmic round hyaline, eosinophilic, and periodic acid Shiff-positive bodies in a lesion frequently otherwise classifiable as meningothelial meningioma. This study reviews the immunohistochemical merlin expression in 14 consecutive secretory meningiomas. Our purpose was to investigate if secretory meningiomas, analogous to meningothelial meningiomas, follow a molecular route of pathogenesis independent of the neurorofibromatosis 2 gene-associated pathway. All meningiomas showed positive immunocoloration involving the majority of the hyaline inclusions and secretory cells; in 12 (86%) meningiomas, a positive immunoreaction was also documented in nonsecretory tumoral cells. Our results may indicate a molecular, besides morphologic, similarity between secretory and meningothelial meningiomas: the almost constant merlin immunohistochemical expression in our series gives evidence for a possible NF2 gene-independent pathogenesis in secretory meningiomas.

Gene expression profiling of metastatic brain cancer

Gene expression profiling of metastatic brain tumors from primary lung adenocarcinoma, using a 17k-expression array, revealed that 1561 genes were consistently altered. Further functional classification placed the genes into seven categories: cell cycle and DNA damage repair, apoptosis, signal transduction molecules, transcription factors, invasion and metastasis, adhesion, and angiogenesis. Genes involved in apoptosis, such as caspase 2 (CASP2), transforming growth factor-beta inducible early gene (TIEG), and neuroprotective heat shock protein 70 (Hsp70) were underexpressed in metastatic brain tumors. Alterations in Rho GTPases (ARHGAP26, ARHGAP1), as well as down-regulation of the metastasis suppressor gene KiSS-1 were noted, which may contribute to tumor aggression. Overexpression of the invasion-related gene neurofibromatosis 1 (NF1), and angiogenesis-related genes vascular endothelial growth factor-B (VEGF-B) and placental growth factor (PGF) was also evidenced. Brain-specific angiogenesis inhibitors 1 and 3 (BAI1 and BAI3) were underexpressed as well. Examination of cell-adhesion and migration-related genes revealed an increased expression of integrins and extracellular matrices collagen and laminin. The study also showed alterations in p53 protein-associated genes, among these increased gene expression of p53, up-regulation of Reprimo or candidate mediator of the p53-dependent G2-arrest, down-regulation of p53-regulated apoptosis-inducing protein 1 (p53AIP1), decreased expression of tumor protein inducible nuclear protein 1 (p53DINP1), and down-regulation of Mdm4 (MDMX). The results demonstrated that genes involved in adhesion, motility, and angiogenesis were consistently up-regulated in metastatic brain tumors, while genes involved in apoptosis, neuroprotection, and suppression of angiogenesis were markedly down-regulated, collectively making these cancer cells prone to metastasis.

Role of NF2 Haploinsufficiency in NF2-associated Polyneuropathy

Neurofibromatosis 2 (NF2) is a hereditary tumor disease characterized by bilateral vestibular schwannomas. Polyneuropathy seems to occur quite frequently in NF2 and in most cases, the etiology of this neuropathy is unclear, especially when the neuropathy is symmetric. NF2 is believed to follow the two-hit hypothesis. According to this, one allele is mutated in the germline, and the second hit is somatic and results in tumor formation. The second hit most frequently is a loss of the NF2 locus, often the entire chromosome 22. We set out to investigate the underlying genetics in peripheral nerve of NF2 patients with polyneuropathy. We identified NF2 patients with polyneuropathy in which we could detect the germline mutation and analyzed NF2 gene dosage in archived nerve biopsies from these patients using a newly developed method. We observed merlin haploinsufficiency in peripheral nerves of two different patients with NF2-related polyneuropathy. This finding was further supported by showing that approximately 50% merlin expression in a cell line using shRNA results in altered gene expression as previously shown in schwannomas. Thus, we suggest that reduced merlin gene dosage is relevant in NF2-associated polyneuropathy.

Life extension through neurofibromin mitochondrial regulation and antioxidant therapy for neurofibromatosis-1 in Drosophila melanogaster

We investigated the pathophysiology of neurofibromatosis-1 (NF1) in Drosophila melanogaster by inactivation or overexpression of the NF1 gene. NF1 gene mutants had shortened life spans and increased vulnerability to heat and oxidative stress in association with reduced mitochondrial respiration and elevated reactive oxygen species (ROS) production. Flies overexpressing NF1 had increased life spans, improved reproductive fitness, increased resistance to oxidative and heat stress in association with increased mitochondrial respiration and a 60% reduction in ROS production. These phenotypic effects proved to be modulated by the adenylyl cyclase/cyclic AMP (cAMP)/protein kinase A pathway, not the Ras/Raf pathway. Treatment of wild-type D. melanogaster with cAMP analogs increased their life span, and treatment of NF1 mutants with metalloporphyrin catalytic antioxidant compounds restored their life span. Thus, neurofibromin regulates longevity and stress resistance through cAMP regulation of mitochondrial respiration and ROS production, and NF1 may be treatable using catalytic antioxidants.

Regulation of the Neurofibromatosis 2 gene promoter expression during embryonic development

Mutations in the Neurofibromatosis 2 (NF2) gene are associated with predisposition to vestibular schwannomas, spinal schwannomas, meningiomas, and ependymomas. Presently, how NF2 is expressed during embryonic development and in the tissues affected by neurofibromatosis type 2 (NF2) has not been well defined. To examine NF2 expression in vivo, we generated transgenic mice carrying a 2.4-kb NF2 promoter driving beta-galactosidase (beta-gal) with a nuclear localization signal. Whole-mount embryo staining revealed that the NF2 promoter directed beta-gal expression as early as embryonic day E5.5. Strong expression was detected at E6.5 in the embryonic ectoderm containing many mitotic cells. beta-gal staining was also found in parts of embryonic endoderm and mesoderm. The beta-gal staining pattern in the embryonic tissues was corroborated by in situ hybridization analysis of endogenous Nf2 RNA expression. Importantly, we observed strong NF2 promoter activity in the developing brain and in sites containing migrating cells including the neural tube closure, branchial arches, dorsal aorta, and paraaortic splanchnopleura. Furthermore, we noted a transient change of NF2 promoter activity during neural crest cell migration. While little beta-gal activity was detected in premigratory neural crest cells at the dorsal ridge region of the neural fold, significant activity was seen in the neural crest cells already migrating away from the dorsal neural tube. In addition, we detected considerable NF2 promoter activity in various NF2-affected tissues such as acoustic ganglion, trigeminal ganglion, spinal ganglia, optic chiasma, the ependymal cell-containing tela choroidea, and the pigmented epithelium of the retina. The NF2 promoter expression pattern during embryogenesis suggests a specific regulation of the NF2 gene during neural crest cell migration and further supports the role of merlin in cell adhesion, motility, and proliferation during development.