Azrieli Research Center of CHU Sainte Justine, University of Montreal, Montreal H3T 1C5, QC, Canada.
Department of Neurosciences, University of Montreal, Montreal H3C 3J7, QC, Canada.
Development. 2024 Nov 1;151(21). doi: 10.1242/dev.202829. Epub 2024 Nov 12.
Congenital scoliosis (CS) is a type of vertebral malformation for which the etiology remains elusive. The notochord is pivotal for vertebrae development, but its role in CS is still understudied. Here, we generated a zebrafish knockout of ptk7a, a planar cell polarity (PCP) gene that is essential for convergence and extension (C&E) of the notochord, and detected congenital scoliosis-like vertebral malformations (CVMs). Maternal zygotic ptk7a mutants displayed severe C&E defects of the notochord. Excessive apoptosis occurred in the malformed notochord, causing a significantly reduced number of vacuolated cells, and compromising the mechanical properties of the notochord. The latter manifested as a less-stiff extracellular matrix along with a significant reduction in the number of the caveolae and severely loosened intercellular junctions in the vacuolated region. These defects led to focal kinks, abnormal mineralization, and CVMs exclusively at the anterior spine. Loss of function of another PCP gene, vangl2, also revealed excessive apoptosis in the notochord associated with CVMs. This study suggests a new model for CS pathogenesis that is associated with defects in notochord C&E and highlights an essential role of PCP signaling in vertebrae development.
先天性脊柱侧凸 (CS) 是一种椎体畸形，其病因仍不清楚。脊索对于椎体发育至关重要，但它在 CS 中的作用仍在研究之中。在这里，我们生成了一种斑马鱼 ptk7a 基因敲除突变体，该基因是平面细胞极性 (PCP) 基因，对于脊索的会聚延伸 (C&E) 至关重要，并检测到先天性脊柱侧凸样椎体畸形 (CVMs)。母源合子 ptk7a 突变体表现出脊索严重的会聚延伸缺陷。畸形脊索中发生了过多的细胞凋亡，导致空泡化细胞的数量显著减少，并损害了脊索的机械性能。后者表现为细胞外基质的硬度降低，以及腔室区域中 caveolae 的数量显著减少和细胞间连接严重松弛。这些缺陷导致了局部扭曲、异常矿化和仅在前脊柱处的 CVMs。另一个 PCP 基因 vangl2 的功能丧失也显示出与 CVMs 相关的脊索中过多的细胞凋亡。这项研究提出了一个与脊索 C&E 缺陷相关的 CS 发病机制的新模型，并强调了 PCP 信号在椎体发育中的重要作用。
