Joubert syndrome is an autosomal recessive disease characterized by midbrain-hindbrain malformation,renal cysts and polydactyly.Inositol polyphosphate 5-phosphatase E,INPP5E,when mutated,is one of causal genes in the Joubert syndrome.However,the downstream pathway of INPP5E in ciliogenesis and polycystic kidney disease(PKD)remains largely unknown.Previous studies indicated that Ezrin,one of the ERM proteins which is activated by PtdIns(4,5)P2,serves as a cross-linker between the plasma membrane and actin cytoskeleton.While PtdIns(4,5)P2 is hydrolyzed by INPP5E,it’s possible that Inpp5e may function through Ezrin to affect ciliogenesis and PKD.Here,we tested this idea.We showed that ezrin is expressed in ciliated organs including olfactory placode,otic vesicle and pronephric duct in zebrafish.Inhibition of ezrin translation by morpholino antisense oligonucleotides caused cystic kidney,body curvature and small eyes.Rescue experiment indicated that both PtdIns(4,5)P2 and actin interacting domains are required for normal function of Ezrin.We further showed that there was ciliogenesis defect as well as disarrangement of basal bodies of multi-ciliated cells in ezrin morphant,which phenocopied the loss of inpp5e.Furthermore,we found there is genetic interaction between ezrin and inpp5e in zebrafish.Also,overexpression of ezrin mRNA can rescue inpp5e morphant phenotypes.Taken together,these results suggested that Inpp5e acts through Ezrin to affect actin organization and finally leads to normal ciliogenesis,which prevents PKD.