Differential effects of human L1CAM mutations on complementing guidance and synaptic defects in Drosophila melanogaster.
Differential effects of human L1CAM mutations on complementing guidance and synaptic defects in Drosophila melanogaster.
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DOI：
10.1371/journal.pone.0076974
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Godenschwege TA
中科院分区：
文献类型：
--
作者：
Kudumala S;Freund J;Hortsch M;Godenschwege TA
已鉴定出大量不同的病理性 L1CAM 突变，这些突变导致广泛的神经和非神经表型。虽然许多这些突变已被表征为它们对同性和异性相互作用以及体外表达水平的影响，但对其体内生物学后果的研究却很少。果蝇中的单个 L1 型 CAM 基因神经胶质细胞 (nrg) 在轴突引导和突触形成过程中具有独特的功能，并且 nrg 突变体的表型可以通过人类 L1CAM 的表达来挽救。我们之前表明，高度保守的细胞内FIGQY锚蛋白结合基序是L1CAM介导的突触形成所必需的，但对于果蝇巨纤维（GF）神经元的神经突生长或轴突引导来说不是必需的。在这里，我们使用 GF 作为模型神经元来表征致病性 L120V、Y1070C、C264Y、H210Q、E309K 和 R184Q 细胞外 L1CAM 错义突变以及具有破坏的埃兹蛋白 - 膜蛋白 - 根蛋白 (ERM) 结合位点的 L1CAM 蛋白，以研究神经元发育的信号传导需求。我们报告不同的 L1CAM 突变对轴突引导和突触形成有不同的影响。此外，L1CAM 通过 ERM 基序的同源性结合和信号传导对于果蝇的轴突引导至关重要。此外，人类病理性 H210Q、R184Q 和 Y1070C，但不影响 E309K 和 L120V L1CAM 突变，会影响突触形成所需的 FigQY 锚蛋白结合域的由外向内信号传导。因此，在人类中观察到的病理表型很可能是由指导和突触发生所需的信号传导破坏引起的。
A large number of different pathological L1CAM mutations have been identified that result in a broad spectrum of neurological and non-neurological phenotypes. While many of these mutations have been characterized for their effects on homophilic and heterophilic interactions, as well as expression levels in vitro, there are only few studies on their biological consequences in vivo. The single L1-type CAM gene in Drosophila, neuroglian (nrg), has distinct functions during axon guidance and synapse formation and the phenotypes of nrg mutants can be rescued by the expression of human L1CAM. We previously showed that the highly conserved intracellular FIGQY Ankyrin-binding motif is required for L1CAM-mediated synapse formation, but not for neurite outgrowth or axon guidance of the Drosophila giant fiber (GF) neuron. Here, we use the GF as a model neuron to characterize the pathogenic L120V, Y1070C, C264Y, H210Q, E309K and R184Q extracellular L1CAM missense mutations and a L1CAM protein with a disrupted ezrin–moesin–radixin (ERM) binding site to investigate the signaling requirements for neuronal development. We report that different L1CAM mutations have distinct effects on axon guidance and synapse formation. Furthermore, L1CAM homophilic binding and signaling via the ERM motif is essential for axon guidance in Drosophila. In addition, the human pathological H210Q, R184Q and Y1070C, but not the E309K and L120V L1CAM mutations affect outside-in signaling via the FIGQY Ankyrin binding domain which is required for synapse formation. Thus, the pathological phenotypes observed in humans are likely to be caused by the disruption of signaling required for both, guidance and synaptogenesis.
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影响因子：
1.9
作者：
Godenschwege TA;Murphey RK
通讯作者：
Murphey RK
影响因子：
9.8
作者：
Enneking EM;Kudumala SR;Moreno E;Stephan R;Boerner J;Godenschwege TA;Pielage J
通讯作者：
Pielage J
影响因子：
4.8
作者：
Lutz, David;Wolters-Eisfeld, Gerrit;Kleene, Ralf
通讯作者：
Kleene, Ralf
影响因子：
11.4
作者：
Castellani, V;De Angelis, E;Rougon, G
通讯作者：
Rougon, G
DOI：
10.1083/jcb.200111076
发表时间：
2002-06-24
期刊：
The Journal of cell biology
影响因子：
--
作者：
Dickson TC;Mintz CD;Benson DL;Salton SR
通讯作者：
Salton SR