当前位置: X-MOL 学术Dev. Cell › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Primary Cilia Signaling Promotes Axonal Tract Development and Is Disrupted in Joubert Syndrome-Related Disorders Models.
Developmental Cell ( IF 10.7 ) Pub Date : 2019-12-16 , DOI: 10.1016/j.devcel.2019.11.005
Jiami Guo 1 , James M Otis 2 , Sarah K Suciu 3 , Christy Catalano 4 , Lei Xing 2 , Sandii Constable 3 , Dagmar Wachten 5 , Stephanie Gupton 2 , Janice Lee 2 , Amelia Lee 2 , Katherine H Blackley 2 , Travis Ptacek 2 , Jeremy M Simon 2 , Stephane Schurmans 6 , Garret D Stuber 7 , Tamara Caspary 3 , E S Anton 2
Affiliation  

Appropriate axonal growth and connectivity are essential for functional wiring of the brain. Joubert syndrome-related disorders (JSRD), a group of ciliopathies in which mutations disrupt primary cilia function, are characterized by axonal tract malformations. However, little is known about how cilia-driven signaling regulates axonal growth and connectivity. We demonstrate that the deletion of related JSRD genes, Arl13b and Inpp5e, in projection neurons leads to de-fasciculated and misoriented axonal tracts. Arl13b deletion disrupts the function of its downstream effector, Inpp5e, and deregulates ciliary-PI3K/AKT signaling. Chemogenetic activation of ciliary GPCR signaling and cilia-specific optogenetic modulation of downstream second messenger cascades (PI3K, AKT, and AC3) commonly regulated by ciliary signaling receptors induce rapid changes in axonal dynamics. Further, Arl13b deletion leads to changes in transcriptional landscape associated with dysregulated PI3K/AKT signaling. These data suggest that ciliary signaling acts to modulate axonal connectivity and that impaired primary cilia signaling underlies axonal tract defects in JSRD.

中文翻译:

原发纤毛信号促进轴突的发展,并在乔伯特综合征相关的疾病模型中被打乱。

适当的轴突生长和连通性对于大脑的功能布线至关重要。Joubert综合征相关疾病(JSRD)是一组纤毛病,其突变破坏了初级纤毛功能,其特征是轴突道畸形。但是,关于纤毛驱动的信号传导如何调节轴突生长和连通性知之甚少。我们证明,在投影神经元中相关的JSRD基因Arl13b和Inpp5e的缺失会导致脱束和方向错误的轴突束。Arl13b缺失破坏了其下游效应子Inpp5e的功能,并解除了睫状PI3K / AKT信号传导。睫状GPCR信号的化学生成激活和下游第二信使级联(PI3K,AKT,和AC3)通常由纤毛信号受体调节,从而引起轴突动力学的快速变化。此外,Arl13b缺失导致与PI3K / AKT信号转导失调相关的转录格局的变化。这些数据表明,纤毛的信号传导可调节轴突的连通性,而初级纤毛信号的受损则是JSRD轴突束缺陷的基础。
更新日期:2019-12-17
down
wechat
bug