脊索通过收敛延伸驱动身体轴的纵向生长,一个高度保守的发育过程,依赖于非规范的Wnt/平面细胞极性(PCP)信号传导。然而,整合素介导的细胞-基质相互作用在脊索发育中的作用尚不清楚.我们开发了转基因Cre小鼠,其中β1整合素基因(Itgb1)仅在脊索或脊索和尾芽中在E8.0处被消融。这些Itgb1条件突变体显示未对齐,畸形椎体,半椎骨和截尾。从早期阶段开始,在这些突变体中,脊索被打断并流离失所。细胞运动缺陷会损害脊索的会聚延伸。用抗β1整合素阻断抗体处理E7.25野生型胚胎,目标节点凹坑单元格,破坏了VANGL2的不对称定位。我们的研究暗示β1整合素在PCP的建立和发育中的脊索的收敛延伸中的关键作用,它的结构完整性和定位,从而确保髓核的发育以及椎体和椎间盘的正确对齐。这种控制的失败可能导致人类先天性脊柱畸形。
The notochord drives longitudinal growth of the body axis by convergent extension, a highly conserved developmental process that depends on non-canonical Wnt/planar cell polarity (PCP) signaling. However, the role of cell-matrix interactions mediated by integrins in the development of the notochord is unclear. We developed transgenic Cre mice, in which the β1 integrin gene (Itgb1) is ablated at E8.0 in the notochord only or in the notochord and tail bud. These Itgb1 conditional mutants display misaligned, malformed vertebral bodies, hemi-vertebrae and truncated tails. From early somite stages, the notochord was interrupted and displaced in these mutants. Convergent extension of the notochord was impaired with defective cell movement. Treatment of E7.25 wild-type embryos with anti-β1 integrin blocking antibodies, to target node pit cells, disrupted asymmetric localization of VANGL2. Our study implicates pivotal roles of β1 integrin for the establishment of PCP and convergent extension of the developing notochord, its structural integrity and positioning, thereby ensuring development of the nucleus pulposus and the proper alignment of vertebral bodies and intervertebral discs. Failure of this control may contribute to human congenital spine malformations.