Oncogenesis of retrovirus induced-glioma and the development of animal model

所谓的禽类胶质瘤(星形细胞瘤)的病因和病理特征尚未确定。我们推测其原因是禽白血病病毒(ALV)的A亚群。本研究旨在阐明禽类胶质瘤诱导病毒(FGV)的致病性，并分析env基因和LTR在神经致病中的分子生物学作用。首先，对实验感染口蹄疫病毒的鸡进行病理检查。其他分离的ALV一般诱发造血肿瘤，而FGV则可能在脑和心脏中复制，并导致神经系统的非化脓性脑炎和心肌炎、神经膜瘤、小脑发育不良和星形细胞瘤。基因组序列分析表明，FGV与几个毒株结合在一起。与其他ALV(登录号为AB112960的EMBL、GenBank和DDBJ核苷酸序列数据库)相比，LTRU3区有几个缺失和几个点突变。LTR的启动子活性也表现出细微的差异，这可能与胶质瘤的诱导有关。此外，51例病变脑组织病理学检查表明，存在一种由星形胶质细胞弥漫性增殖组成的组织学变异，并提示该疾病实体应命名为“逆转录病毒诱导的鸡星形细胞瘤”。为了检测口蹄疫病毒LTR启动子在体内的活性，建立了13个在LTR启动子控制下表达转基因小鼠的品系，并通过逆转录-聚合酶链式反应(RT-PCR)检测每个品系中的mRNA，分析了转基因小鼠表达的组织特异性。结果表明，尽管FGV LTR启动子在体内是一个全特异性启动子，但该启动子能够驱动转基因在中枢神经系统和睾丸中的稳定表达。

The cause and pathological features of so-called fowl glioma (astrocytoma) had not been determined. We have suggested that the cause is a subgroup A of avian leukosis virus (ALV). The subject of this research project is to clarify the pathogenicity of fowl glioma-inducing virus (FGV) and to analyze the molecular biological role of env gene and LTR in the neuropathogenicity. At first, chickens experimentally infected with FGV were pathologically examined. Whereas other isolated ALVs generally induce hematopoietic neoplasms, FGV was likely to replicate especially in brain and heart and induced nonsuppurative encephalitis and myocarditis, perineurioma, cerebellar hypoplasia as well as astrocytoma in nervous system. Genome sequence analysis suggested FGV to be combined with several virus strains. The U3 region of the LTR had a few deletions and several point mutations compared to that of other ALVs (EMBL, GenBank, and DDBJ nucleotide sequence databases under the accession number AB112960). The promoter activity of LTR also showed subtle differences, which may be related to the induction of glial neoplasm. In addition, histopathology of the 51 affected brains suggested the presence of a histological variant composed of diffuse proliferation of astrocytes and indicated that the disease entity should be named "retrovirus-induced astrocytoma" of chickens. To examine the promoter activity of FGV LTR in vivo, 13 lines of transgenic mice expressing a transgene under the control of the LTR promoter were generated and the tissue specificity of the expression was analyzed by monitoring mRNA in each line using the reverse transcription-polymerase chain reaction. The results indicated that the FGV LTR promoter was capable of driving a stable transgene expression especially in the central nervous system and testis although the LTR acted as a panspecific promoter in vivo.