The neurofibromatosis-2 homologue, Merlin, and the tumor suppressor expanded function together in Drosophila to regulate cell proliferation and differentiation.
The neurofibromatosis-2 homologue, Merlin, and the tumor suppressor expanded function together in Drosophila to regulate cell proliferation and differentiation.
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发表时间：
2000-03
期刊：
影响因子：
4.6
通讯作者：
B. McCartney;R. Kulikauskas;D. LaJeunesse;R. Fehon
中科院分区：
文献类型：
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作者：
B. McCartney;R. Kulikauskas;D. LaJeunesse;R. Fehon
神经纤维瘤病-2是一种遗传性疾病，其特征是良性神经鞘瘤和其他与中枢神经系统相关的神经鞘细胞源性肿瘤的发展。神经纤维瘤病-2肿瘤抑制基因编码Merlin，Merlin是与Ezrin、Radixin和Moesin最密切相关的蛋白质4.1超家族的成员。这一发现表明蛋白质4.1家族成员在调节细胞增殖中具有新的功能;该家族中的蛋白质先前被认为主要功能是将跨膜蛋白连接到底层皮质肌动蛋白。为了了解Merlin的基本细胞功能，我们正在研究果蝇神经纤维瘤病-2同源物Merlin。果蝇中Merlin功能的丧失导致受影响组织的增生，而不显著破坏分化。在果蝇的另一个蛋白质4.1超家族成员的突变中也观察到了类似的表型。由于Merlin和Expanded之间的表型和结构相似性，我们询问Merlin和Expanded是否一起调节细胞增殖。在这项研究中，我们证明，无论是默林或扩大的功能的隐性损失可以显性增强与其他突变相关的表型。与这种遗传相互作用相一致，我们确定Merlin和Expanded在果蝇组织和细胞中共定位，并通过蛋白4.1家族特有的Expanded保守的N-末端区域和Merlin的C-末端结构域进行物理相互作用。Merlin和扩增克隆的功能丧失表明，这些蛋白除了在果蝇中调节增殖外，还调节分化。进一步的遗传分析表明Merlin和Expanded在十肢瘫痪介导的分化事件中具有特异性作用。这些结果表明Merlin和Expanded共同调节增殖和分化，并对理解其他蛋白4.1超家族成员的功能具有意义。
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.