ptk7 mutant zebrafish models of congenital and idiopathic scoliosis implicate dysregulated Wnt signalling in disease.
ptk7 mutant zebrafish models of congenital and idiopathic scoliosis implicate dysregulated Wnt signalling in disease.
复制标题
DOI：
10.1038/ncomms5777
复制
发表时间：
2014-09-03
影响因子：
16.6
通讯作者：
Ciruna, Brian
中科院分区：
文献类型：
--
作者：
Hayes, Madeline;Gao, Xiaochong;Yu, Lisa X.;Paria, Nandina;Henkelman, R. Mark;Wise, Carol A.;Ciruna, Brian
脊柱侧凸是一种复杂的肌肉骨骼系统遗传性疾病，其特征在于脊柱的三维旋转。由畸形椎骨（先天性脊柱侧凸（CS））引起的弯曲在出生时就很明显。脊柱弯曲，没有潜在的脊椎异常（特发性脊柱侧凸（IS））最常见的表现在青春期。负责IS的遗传和生物学机制仍然知之甚少，主要是由于有限的实验模型。在这里，我们描述合子ptk7（Zptk7）突变斑马鱼，缺乏Wnt信号的关键调节，作为第一个遗传定义的发展模式的IS。我们确定了一个新的序列变异在一个单一的IS患者，破坏PTK7功能，与疾病发病机制中的Wnt活性失调的作用一致。此外，我们表明，胚胎丢失的基因功能的母合子ptk7突变体（MZptk7）导致脊椎异常与CS。我们的数据表明，先天性和特发性疾病的新的分子起源和遗传联系。 脊柱侧凸是一种复杂的遗传性疾病，其特征是脊柱弯曲。在这里，作者提出了特发性和先天性脊柱侧凸的实验斑马鱼模型，并提出了脊柱侧凸病因学中Wnt活性失调的作用。
Scoliosis is a complex genetic disorder of the musculoskeletal system, characterized by three-dimensional rotation of the spine. Curvatures caused by malformed vertebrae (congenital scoliosis (CS)) are apparent at birth. Spinal curvatures with no underlying vertebral abnormality (idiopathic scoliosis (IS)) most commonly manifest during adolescence. The genetic and biological mechanisms responsible for IS remain poorly understood due largely to limited experimental models. Here we describe zygotic ptk7 (Zptk7) mutant zebrafish, deficient in a critical regulator of Wnt signalling, as the first genetically defined developmental model of IS. We identify a novel sequence variant within a single IS patient that disrupts PTK7 function, consistent with a role for dysregulated Wnt activity in disease pathogenesis. Furthermore, we demonstrate that embryonic loss-of-gene function in maternal-zygotic ptk7 mutants (MZptk7) leads to vertebral anomalies associated with CS. Our data suggest novel molecular origins of, and genetic links between, congenital and idiopathic forms of disease. Scoliosis is a complex genetic disorder characterized by spinal curvature. Here, the authors present experimental zebrafish models of idiopathic and congenital scoliosis and suggest a role for dysregulated Wnt activity in scoliosis aetiology.
登录
查看更多内容
影响因子：
3.2
作者：
Giampietro PF
通讯作者：
Giampietro PF
影响因子：
64.8
作者：
Kawakami, Y;Raya, A;Belmonte, JCI
通讯作者：
Belmonte, JCI
影响因子：
4.6
作者：
Hayes, Madeline;Naito, Mizue;Ciruna, Brian
通讯作者：
Ciruna, Brian
影响因子：
56.9
作者：
Giraldez, AJ;Mishima, Y;Schier, AF
通讯作者：
Schier, AF
影响因子：
30.8
作者：
Bulman, MP;Kusumi, K;Turnpenny, PD
通讯作者：
Turnpenny, PD