McCartney B M, Kulikauskas R M, LaJeunesse D R, Fehon R G
Developmental, Cell and Molecular Biology Group, Duke University, Durham, NC 27708-1000, USA.
Development. 2000 Mar;127(6):1315-24. doi: 10.1242/dev.127.6.1315.
Neurofibromatosis-2 is an inherited disorder characterized by the development of benign schwannomas and other Schwann-cell-derived tumors associated with the central nervous system. The Neurofibromatosis-2 tumor suppressor gene encodes Merlin, a member of the Protein 4.1 superfamily most closely related to Ezrin, Radixin and Moesin. This discovery suggested a novel function for Protein 4.1 family members in the regulation of cell proliferation; proteins in this family were previously thought to function primarily to link transmembrane proteins to underlying cortical actin. To understand the basic cellular functions of Merlin, we are investigating a Drosophila Neurofibromatosis-2 homologue, Merlin. Loss of Merlin function in Drosophila results in hyperplasia of the affected tissue without significant disruptions in differentiation. Similar phenotypes have been observed for mutations in another Protein 4.1 superfamily member in Drosophila, expanded. Because of the phenotypic and structural similarities between Merlin and expanded, we asked whether Merlin and Expanded function together to regulate cell proliferation. In this study, we demonstrate that recessive loss of function of either Merlin or expanded can dominantly enhance the phenotypes associated with mutations in the other. Consistent with this genetic interaction, we determined that Merlin and Expanded colocalize in Drosophila tissues and cells, and physically interact through a conserved N-terminal region of Expanded, characteristic of the Protein 4.1 family, and the C-terminal domain of Merlin. Loss of function of both Merlin and expanded in clones revealed that these proteins function to regulate differentiation in addition to proliferation in Drosophila. Further genetic analyses suggest a role for Merlin and Expanded specifically in Decapentaplegic-mediated differentiation events. These results indicate that Merlin and Expanded function together to regulate proliferation and differentiation, and have implications for understanding the functions of other Protein 4.1 superfamily members.
神经纤维瘤病2型是一种遗传性疾病，其特征是会出现良性施万细胞瘤以及其他与中枢神经系统相关的源自施万细胞的肿瘤。神经纤维瘤病2型肿瘤抑制基因编码Merlin，它是4.1蛋白超家族的成员，与埃兹蛋白、根蛋白和膜突蛋白关系最为密切。这一发现提示了4.1蛋白家族成员在细胞增殖调控方面的新功能；此前认为该家族中的蛋白质主要作用是将跨膜蛋白与下方的皮质肌动蛋白相连。为了解Merlin的基本细胞功能，我们正在研究果蝇神经纤维瘤病2型的同源物Merlin。果蝇中Merlin功能缺失会导致受影响组织增生，且分化无明显破坏。在果蝇中，另一个4.1蛋白超家族成员expanded发生突变也观察到了类似的表型。由于Merlin和expanded在表型和结构上存在相似性，我们探究了Merlin和Expanded是否共同发挥作用来调控细胞增殖。在本研究中，我们证明Merlin或expanded的隐性功能缺失都能显性增强与另一个基因的突变相关的表型。与这种遗传相互作用一致，我们确定Merlin和Expanded在果蝇组织和细胞中共定位，并通过Expanded保守的N端区域（4.1蛋白家族的特征）和Merlin的C端结构域发生物理相互作用。克隆中Merlin和expanded功能均缺失表明，在果蝇中这些蛋白质除了调控增殖外还参与调控分化。进一步的遗传分析表明Merlin和Expanded在特定的由骨形态发生蛋白信号通路介导的分化事件中发挥作用。这些结果表明Merlin和Expanded共同发挥作用来调控增殖和分化，这对于理解其他4.1蛋白超家族成员的功能具有重要意义。
