The zebrafish candyfloss mutant implicates extracellular matrix adhesion failure in laminin α2-deficient congenital muscular dystrophy
The zebrafish candyfloss mutant implicates extracellular matrix adhesion failure in laminin α2-deficient congenital muscular dystrophy
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DOI：
10.1073/pnas.0700942104
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发表时间：
2007-04-24
影响因子：
11.1
通讯作者：
Currie, Peter D.
中科院分区：
文献类型：
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作者：
Hall, Thomas E.;Bryson-Richardson, Robert J.;Currie, Peter D.
人层粘连蛋白α 2（LAMA 2）基因突变导致最常见的先天性肌营养不良症（MDC 1A）。目前存在三种用于MDC 1A中细胞病理学的分子基础的模型：（i）LAMA 2的缺乏导致肌膜虚弱和衰竭，随后是细胞坏死，如杜氏肌营养不良症（DMD）中的情况;（ii）在肌肉组织的发育和维持期间LAMA 2介导的信号传导的丧失导致成肌细胞增殖和融合缺陷;（M）LAMA 2从周围神经周围的许旺细胞的基底膜的损失导致缺乏运动刺激，导致有效的去神经萎缩。在这里，我们表明，在斑马鱼的营养不良突变体，candyfloss（猫）的结果层粘连蛋白α 2（lama 2）基因突变的退化肌肉表型。在体内的时间推移分析机械加载的纤维和膜通透性测定表明，与DMID，纤维脱离最初与肌膜破裂。早期肌肉形成和成肌细胞融合是正常的，表明早期Lama 2信号传导的任何缺陷都不会导致肌肉病理学。此外，初级运动神经元的神经支配不受影响，并且纤维脱离源于肌肉收缩，这表明由于缺乏运动神经元活性而导致的肌肉萎缩不会导致该系统的病理学。使用这些和其他分析，我们提出了一个模型lama 2的功能，其中纤维脱离肌膜外部的机械诱导，和收缩的纤维与未受损的膜进行随后的细胞凋亡。
Mutations in the human laminin alpha 2 (LAMA2) gene result in the most common form of congenital muscular dystrophy (MDC1A). There are currently three models for the molecular basis of cellular pathology in MDC1A: (i) lack of LAMA2 leads to sarcolemmal weakness and failure, followed by cellular necrosis, as is the case in Duchenne muscular dystrophy (DMD); (ii) loss of LAMA2-mediated signaling during the development and maintenance of muscle tissue results in myoblast proliferation and fusion defects; (M) loss of LAMA2 from the basement membrane of the Schwann cells surrounding the peripheral nerves results in a lack of motor stimulation, leading to effective denervation atrophy. Here we show that the degenerative muscle phenotype in the zebrafish dystrophic mutant, candyfloss (cat) results from mutations in the laminin alpha 2 (lama2) gene. In vivo time-lapse analysis of mechanically loaded fibers and membrane permeability assays suggest that, unlike DMID, fiber detachment is not initially associated with sarcolemmal rupture. Early muscle formation and myoblast fusion are normal, indicating that any deficiency in early Lama2 signaling does not lead to muscle pathology. in addition, innervation by the primary motor neurons is unaffected, and fiber detachment stems from muscle contraction, demonstrating that muscle atrophy through lack of motor neuron activity does not contribute to pathology in this system. Using these and other analyses, we present a model of lama2 function where fiber detachment external to the sarcolemma is mechanically induced, and retracted fibers with uncompromised membranes undergo subsequent apoptosis.