Telencephalic morphogenesis is impaired in Ftm/Rpgrip1l KO mice

摘要

Primary cilia have essential functions in vertebrate developmentand signaling. However, little is known aboutcilia function in brain morphogenesis, a process that isseverely affected in human ciliopathies. Here, we studytelencephalic morphogenesis in a mouse mutant for theciliopathy gene Ftm/Rpgrip1l (also called NPHP8, JBTS7or MKS5). We have previously shown that E12.5 Ftm-/-telencephalic neuroepithelial cells lack primary cilia andthat the telencephalon is ventralized at this stage. Thisdorso-ventral (DV) patterning defect leads to an ectopiclocalization of the olfactory bulb primordium, which consequentlydoes not display morphological outgrowth atthe end of gestation. This phenotype is reminiscent ofGli3 mutant and indeed correlates with a decreased productionof the short, repressor form of Gli3 (Gli3R). Wethen demonstrate that the main function of primary ciliain the developing brain is to permit Gli3 prossessing,since introduction of Gli3R in Ftm-/- backgroung is sufficientto rescue DV patterning and OB morphologicaldefects, despite the persistence of the cilia defects. Inaddition, we observed an impairement of the neocortexin Ftm mutant at the end of gestation. Cortical laminationis impaired, showing patches of very abnormalregions lying between regions that are less severelyaffected. This heterogeneity correlates with a disorganizationof radial glial fibres and a reduction of the thicknessof the ventricular layers and of the cortical plate. Investigatingthe developmental origin of these defects shouldshed light on aspects of physiopathology in humandiseases.