Zebrafish neurofibromatosis type 1 genes have redundant functions in tumorigenesis and embryonic development
Jimann ShinArun PadmanabhanEric D. de GrohJeong-Soo LeeSam HaidarSuzanne E. DahlbergFeng GuoShuning HeMarc A. WolmanMichael GranatoNathan D. LawsonScot A. WolfeSeok‐Hyung KimLilianna Solnica‐KrezelJohn P. KankiKeith L. LigonJonathan A. EpsteinA. Thomas Look
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Summary Neurofibromatosis type 1 (NF1) is a common, dominantly inherited genetic disorder that results from mutations in the neurofibromin 1 (NF1) gene. Affected individuals demonstrate abnormalities in neural crest-derived tissues that include hyperpigmented skin lesions and benign peripheral nerve sheath tumors. NF1 patients also have a predisposition to malignancies including juvenile myelomonocytic leukemia (JMML), optic glioma, glioblastoma, schwannoma, and malignant peripheral nerve sheath tumors (MPNSTs). In an effort to better define the molecular and cellular determinants of NF1 disease pathogenesis in vivo, we employed targeted mutagenesis strategies to generate zebrafish harboring stable germline mutations in nf1a and nf1b, orthologues of NF1. Animals homozygous for loss-of-function alleles of nf1a or nf1b alone are phenotypically normal and viable. Homozygous loss of both alleles in combination generates larval phenotypes that resemble aspects of the human disease and results in larval lethality between 7 and 10 days post fertilization. nf1-null larvae demonstrate significant central and peripheral nervous system defects. These include aberrant proliferation and differentiation of oligodendrocyte progenitor cells (OPCs), dysmorphic myelin sheaths, and hyperplasia of Schwann cells. Loss of nf1 contributes to tumorigenesis as demonstrated by an accelerated onset and increased penetrance of high-grade gliomas and MPNSTs in adult nf1a+/-; nf1b-/-; p53e7/e7 animals. nf1-null larvae also demonstrate significant motor and learning defects. Importantly, we identify and quantitatively analyze a novel melanophore phenotype in nf1-null larvae, providing the first animal model of the pathognomonic pigmentation lesions of NF1. Together, these findings support a role for nf1a and nf1b as potent tumor suppressor genes that also function in the development of both central and peripheral glial cells as well as melanophores in zebrafish.Keywords:
Neurofibromin 1
Neurofibromatosis type 1, the most common phakomatoses, can present with a host of signs and symptoms, usually involving the skin and the peripheral nervous system. It is characterized by a mutation in the neurofibromatosis type 1 gene on chromosome 17q11.2 that codes for the protein neurofibromin. Neurofibromin acts as a tumor suppressor gene by inhibiting rat sarcoma (Ras) activity and its deficiency leads to increased Ras activity, cellular proliferation and tumor formation. This review was conducted to analyze the various targeted therapies at the genetic and molecular level employed to manage the tumors and other clinical presentations associated with neurofibromatosis type 1. Twenty-eight studies of treatment modalities for the conditions associated with neurofibromatosis and which involved either targeted gene therapy or molecular level therapies, including the latest advances, were included in this review. Mitogen-activated protein kinase kinase inhibition, mammalian target of Rapamycin inhibition and Tyrosine kinase inhibition, represent some of the newer treatment options in this category. Although there are a number of trials for providing therapeutic options at the genetic and molecular level for the various physical and psychological morbidities associated with neurofibromatosis type 1, most of them are in the preclinical stage. Increased clinical trials of the molecules and gene therapies could significantly help in managing the various chronic and sometimes, life-threatening conditions associated with neurofibromatosis 1 and these will probably represent the preferred treatment direction of the future.
Neurofibromin 1
Neurofibromatosis type I
Neurofibromatoses
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1. We analysed the expression of neurofibromin mRNAs, encoded by the gene responsible for neurofibromatosis type 1, and of neurofibromin protein in nine soft tissue tumours by S1 nuclease mapping and Western blot analyses. Four tumours were obtained from patients with neurofibromatosis type 1, comprising two neurofibromas, one fibrolipoma and one malignant schwannoma, and five neurogenic tumours were obtained from non-neurofibromatosis type 1 patients. 2. All tumours, except for a malignant schwannoma, similarly expressed three species of mRNA encoding neurofibromin, an isoform with the insertion of 21 amino acids in the domain related to ras GTPase-activating protein, and an N-terminal isoform lacking this domain. 3. Western blot analysis demonstrated deficiency of neurofibromin in the tumours derived from three out of the four neurofibromatosis type 1 patients: a fibrolipoma, a malignant schwannoma and a neurofibroma. In contrast, reduction in neurofibromin was not detected in the five tumours obtained from non-neurofibromatosis type 1 patients. Furthermore, the expression of ras GTPase-activating protein was detected in all nine tumours examined. 4. The undetectable or reduced level of neurofibromin in the tumours obtained from neurofibromatosis type 1 patients suggests that this deficiency is closely related to their tumourigenesis.
Neurofibromin 1
Neurofibromatosis type I
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Neurofibromatosis type 1 (NF1) is one of the most common neurocutaneus disorders. NF1 is caused by defects in the NF1 gene, coding for the neurofibromin protein which acts as a tumor suppressor. The inheritance of NF1 is autosomal dominant.
Neurofibromin 1
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Aim:To investigate the differences in the expression of neurofibromin and Ras-p21 in neurofibromas tissue of neurofibromatosis type1(NF1) and solitary neurofibroma(SNF).Methods:The expression of neurofibromin and Ras-p21 protein in neurofibromas tissue from 19 cases of NF1 and 16 cases of SNF were detected using Western-blot.11 cases of normal nerve tissue were the control.Results: The expression of neurofibromin in neurofibromas tissue from NF1 group was significant lower than those from SNF group and the control group (P0.05), while the expression of Ras-p21 protein was higher than those from SNF group and the control group (P0.05). No difference in the expressions of neurofibromin and Ras-p21 between the SNF group and the control group were found.Conclusion:NF1 gene leading to the deletion of neurofibromin which resulted in the deletion of Ras-p21 may be involved into the NF1 pathogenesis.The detection of neurofibromin may be helpful for NF1 diagnosis and differentiation to SNF.
Neurofibromin 1
Pathogenesis
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Neurofibromatosis type 1 (NF1) or von Recklinghausen neurofibromatosis is a common autosomal dominant disorder affecting 1 in 3000 individuals. The gene for NF1 is localized on chromosome 17q11.2. The gene mutations or the inactivation its protein product--neurofibromin are responsible for the manifestation of the disease. NF1 demonstrates a wide variability of clinical symptoms classified by NIH Consensus Conference in 1987.
Neurofibromin 1
Pathogenesis
Neurofibromatosis type I
Inherited disease
Neurofibromatoses
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Neurofibromatosis 1 is one of the most common autosomal dominant disorders affecting the nervous system. Individuals with neurofibromatosis 1 present with abnormalities of both astrocytes and neurons that result from reduced or absent expression of the NF1 gene product neurofibromin. Impaired neurofibromin function in these nervous system cells contributes to the development of astrocytomas, learning disabilities, and radiographic abnormalities of the brain. With the identification of NF1 , significant advances have begun to unlock some of the mysteries that surround the molecular pathogenesis of neurofibromatosis 1-associated brain abnormalities. With continued advances in our basic understanding of NF1 function, future targeted therapies for neurofibromatosis 1-associated central nervous system abnormalities can be developed. (J Child Neurol 2002;17:592-601).
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Neurofibromatosis is one of the most common genetic diseases. It is inherited in an autosomal dominant manner. It is divided into two genetically distinct subtypes, characterised by multiple skin lesions and tumours of the peripheral and central nervous system. Neurofibromatosis type 1, or Recklinghausen's disease, is the most common phakomatosis. The disease is genetically determined by a mutation of the neurofibromin- 1 gene on chromosome 17. Neurofibromatosis type 2 accounts for 3% of all cases. The disease is genetically determined - caused by a mutation of the neurofibromin-2 gene on chromosome 22. The diagnostic and therapeutic process of neurofibromatosis is a major challenge for clinicians. Given the complexity of the problem, we have reviewed the literature on the diagnostic and therapeutic possibilities of the disease.
Neurofibromin 1
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Neurofibromatosis 类型 1 是有外显率的高率的普通正染色体的主导的混乱。它被肿瘤的变化引起压制或基因 NF1，它编码 neurofibromin。neurofibromin 的主要功能是下面调整的由充当激活蛋白质的地岬特定的 GTPase 的 proto-oncoprotein 地岬的生物学的活性。在这研究，我们鉴别与 neurofibromatosis 影响的一个中国家庭打 1。与 NF1 联系的已知的基因 NF1 被连接分析并且由全部编码区域和 NF1 基因的 exon-intron 边界的直接定序学习。NF1 的 R1947X 变化被识别，它在未受影响的家庭成员在中国家庭，然而并非礼品与影响个人一起被共同分离。这是第一份报告，它声明 NF1 的 R1947X 变化可以是为在中国人口的 neurofibromatosis 类型 1 的原因之一。
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Intrinsic lesions of arterial walls are an important manifestation of neurofibromatosis 1 (NF1). Neurofibromin is expressed in blood vessel endothelial and smooth muscle cells, and NF1 vasculopathy may result from an alteration of neurofibromin function in these cells. Elucidation of the role of neurofibromin in the maintenance and repair of blood vessels may lead to novel approaches to the treatment of NF1 vasculopathy and vascular disease in general.
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Pathogenesis
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