Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas 77843-2128.
Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas 77843-2128
J Neurosci. 2018 Feb 14;38(7):1850-1865. doi: 10.1523/JNEUROSCI.0346-17.2017. Epub 2017 Nov 22.
Genetic defects in protein O-mannosyltransferase 1 (POMT1) and POMT2 underlie severe muscular dystrophies. genes are evolutionarily conserved in metazoan organisms. In , both male and female mutants show a clockwise rotation of adult abdominal segments, suggesting a chirality of underlying pathogenic mechanisms. Here we described and analyzed a similar phenotype in mutant embryos that shows left-handed body torsion. Our experiments demonstrated that coordinated muscle contraction waves are associated with asymmetric embryo rolling, unveiling a new chirality marker in development. Using genetic and live-imaging approaches, we revealed that the torsion phenotype results from differential rolling and aberrant patterning of peristaltic waves of muscle contractions. Our results demonstrated that peripheral sensory neurons are required for normal contractions that prevent the accumulation of torsion. We found that mutants show abnormal axonal connections of sensory neurons. transgenic expression limited to sensory neurons significantly rescued the torsion phenotype, axonal connectivity defects, and abnormal contractions in mutant embryos. Together, our data suggested that protein O-mannosylation is required for normal sensory feedback to control coordinated muscle contractions and body posture. This mechanism may shed light on analogous functions of genes in mammals and help to elucidate the etiology of neurological defects in muscular dystrophies. Protein O-mannosyltransferases (POMTs) are evolutionarily conserved in metazoans. Mutations in cause severe muscular dystrophies associated with pronounced neurological defects. However, neurological functions of POMTs remain poorly understood. We demonstrated that mutations in result in abnormal muscle contractions and cause embryo torsion. Our experiments uncovered a chirality of embryo movements and a unique -dependent mechanism that maintains symmetry of a developing system affected by chiral forces. Furthermore, were found to be required for proper axon connectivity of sensory neurons, suggesting that O-mannosylation regulates the sensory feedback controlling muscle contractions. This novel POMT function in the peripheral nervous system may shed light on analogous functions in mammals and help to elucidate pathomechanisms of neurological abnormalities in muscular dystrophies.
蛋白-O-甘露糖基转移酶 1（POMT1）和 POMT2 的遗传缺陷导致严重的肌肉营养不良。这些基因在后生动物中是进化保守的。在果蝇中，雄性和雌性突变体都表现出成年腹部节段的顺时针旋转，表明潜在致病机制存在手性。在这里，我们描述并分析了 突变体胚胎中类似的表型，该表型显示出左手扭曲。我们的实验表明，协调的肌肉收缩波与不对称的胚胎滚动有关，揭示了 发育中的一个新的手性标记。使用遗传和活体成像方法，我们揭示了扭曲表型是由于肌肉收缩的蠕动波的差异滚动和异常模式化。我们的结果表明，外围感觉神经元对于防止扭曲积累的正常收缩是必需的。我们发现，突变体显示出感觉神经元的异常轴突连接。将 转基因表达仅限于感觉神经元，可显著挽救 突变体胚胎中的扭曲表型、轴突连接缺陷和异常收缩。总之，我们的数据表明，蛋白-O-甘露糖化对于正常感觉反馈以控制协调的肌肉收缩和身体姿势是必需的。该机制可能阐明了 基因在哺乳动物中的类似功能，并有助于阐明肌肉营养不良中神经缺陷的病因。蛋白-O-甘露糖基转移酶（POMTs）在后生动物中是进化保守的。 基因突变导致与明显神经缺陷相关的严重肌肉营养不良。然而，POMTs 的神经功能仍知之甚少。我们证明， 基因突变导致肌肉收缩异常，并导致胚胎扭曲。我们的实验揭示了胚胎运动的手性和一种独特的依赖于 的机制，该机制维持了受手性力影响的发育系统的对称性。此外，发现 对于感觉神经元的适当轴突连接是必需的，这表明 O-甘露糖化调节控制肌肉收缩的感觉反馈。这种在周围神经系统中的新型 POMT 功能可能阐明了哺乳动物中的类似功能，并有助于阐明肌肉营养不良中神经异常的病理机制。
