Gutmann D H, Cole J L, Collins F S
Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
Prog Brain Res. 1995;105:327-35. doi: 10.1016/s0079-6123(08)63311-7.
The von Recklinghausen neurofibromatosis type 1 (NF1) gene was identified by positional cloning and found to be a tumor suppressor gene expressed most abundantly in brain. One isoform of NF1 (type 2 NF1) contains an additional 21 amino acids inserted into a region of the protein involved in the regulation of p21-ras. To study the role of the NF1 gene in mammalian development, the expression of the NF1 gene and protein product, neurofibromin, during mouse embryonic development was determined. NF1 mRNA and neurofibromin expression was detectable by Northern and Western analysis, respectively, after day 10 of murine embryogenesis and remained elevated throughout development. Type 2 NF1 mRNA expression predominated before day 10, after which time, type 1 (lacking the insertion) NF1 mRNA was the predominant isoform detected. The protein expression of the type 2 isoform was similar to overall neurofibromin expression by Western blot analysis with greatest expression in adult brain. Despite a similar tissue distribution pattern, type 2 neurofibromin was not found to be associated with brain cytoplasmic microtubules in the same fashion as the uninserted type 1 isoform. Collectively, these experiments suggest that the switch from type 2 to type 1 neurofibromin isoform predominance during embryogenesis may have significant functional consequences.
1型冯雷克林霍增氏神经纤维瘤病（NF1）基因通过定位克隆被鉴定出来，发现它是一种在脑中表达最为丰富的肿瘤抑制基因。NF1的一种同工型（2型NF1）在参与调控p21 - ras的蛋白质区域插入了额外的21个氨基酸。为了研究NF1基因在哺乳动物发育中的作用，测定了NF1基因及其蛋白质产物神经纤维瘤蛋白在小鼠胚胎发育过程中的表达情况。在小鼠胚胎发育第10天后，分别通过Northern分析和Western分析可检测到NF1 mRNA和神经纤维瘤蛋白的表达，并且在整个发育过程中一直保持较高水平。在第10天之前，2型NF1 mRNA表达占主导，之后，检测到的主要同工型是1型（无插入）NF1 mRNA。通过Western印迹分析，2型同工型的蛋白质表达与整体神经纤维瘤蛋白表达相似，在成体脑中表达最高。尽管组织分布模式相似，但未发现2型神经纤维瘤蛋白与脑细胞质微管的结合方式与未插入的1型同工型相同。总的来说，这些实验表明在胚胎发育过程中从2型到1型神经纤维瘤蛋白同工型优势的转变可能具有重大的功能后果。
