汇聚延伸运动和纤毛功能由ofd1介导,ofd1是人类口面指综合征1型基因在斑马鱼中的同源基因。

Convergent extension movements and ciliary function are mediated by ofd1, a zebrafish orthologue of the human oral-facial-digital type 1 syndrome gene.

作者信息

Ferrante Maria I, Romio Leila, Castro Silvia, Collins John E, Goulding David A, Stemple Derek L, Woolf Adrian S, Wilson Stephen W

机构信息

Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SA, UK.

出版信息

Hum Mol Genet. 2009 Jan 15;18(2):289-303. doi: 10.1093/hmg/ddn356. Epub 2008 Oct 29.

Abstract

In humans, OFD1 is mutated in oral-facial-digital type I syndrome leading to prenatal death in hemizygous males and dysmorphic faces and brain malformations, with polycystic kidneys presenting later in life in heterozygous females. To elucidate the function of Ofd1, we have studied its function during zebrafish embryonic development. In wild-type embryos, ofd1 mRNA is widely expressed and Ofd1-green fluorescent protein (GFP) fusion localizes to the centrosome/basal body. Disrupting Ofd1 using antisense morpholinos (MOs) led to bent body axes, hydrocephalus and oedema. Laterality was randomized in the brain, heart and viscera, likely a consequence of shorter cilia with disrupted axonemes and perturbed intravesicular fluid flow in Kupffer's vesicle. Embryos injected with ofd1 MOs also displayed convergent extension (CE) defects, which were enhanced by loss of Slb/Wnt11 or Tri/Vangl2, two proteins functioning in a non-canonical Wnt/Planar Cell Polarity (PCP) pathway. Pronephric glomerular midline fusion was compromised in vangl2 and ofd1 loss of function embryos and we suggest this anomaly may be a novel CE defect. Thus, Ofd1 is required for ciliary motility and function in zebrafish, supporting data showing that Ofd1 is essential for primary cilia function in mice. In addition, our data show that Ofd1 is important for CE during gastrulation, consistent with data linking primary cilia and non-canonical Wnt/PCP signalling.

摘要

在人类中,OFD1基因发生突变会导致I型口面指综合征,半合子男性会出现产前死亡,面部畸形和脑畸形,杂合子女性则在生命后期出现多囊肾。为了阐明Ofd1的功能,我们研究了它在斑马鱼胚胎发育过程中的作用。在野生型胚胎中,ofd1 mRNA广泛表达,Ofd1-绿色荧光蛋白(GFP)融合蛋白定位于中心体/基体。使用反义吗啉代寡核苷酸(MOs)破坏Ofd1会导致身体轴弯曲、脑积水和水肿。大脑、心脏和内脏的左右不对称性随机化,这可能是由于纤毛较短,轴丝破坏以及库普弗小泡内的囊泡液流动受到干扰所致。注射ofd1 MOs的胚胎也表现出原肠胚形成期汇聚延伸(CE)缺陷,在Slb/Wnt11或Tri/Vangl2缺失时这种缺陷会增强,这两种蛋白在非经典Wnt/平面细胞极性(PCP)途径中发挥作用。在vangl2和ofd1功能缺失的胚胎中,前肾肾小球中线融合受损,我们认为这种异常可能是一种新的CE缺陷。因此,Ofd1在斑马鱼中是纤毛运动和功能所必需的,这支持了Ofd1对小鼠初级纤毛功能至关重要的数据。此外,我们的数据表明Ofd1在原肠胚形成期对CE很重要,这与将初级纤毛和非经典Wnt/PCP信号联系起来的数据一致。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dbf9/2638777/75690f8a5b15/ddn35601.jpg

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