Ofd1 controls dorso-ventral patterning in the brain and plays a developmental stage dependent role in ciliogenesis.

Oral-facial-digital type I syndrome (OFDI) is a human X-linked dominantmale-lethal developmental disorder caused by mutations in the OFD1 transcript.Similar to other inherited disorders associated to ciliary dysfunctionOFDI patients display neurological abnormalities. We therefore characterizedthe neuronal phenotype resulting from Ofd1 inactivation in early phases of mouse embryonic development and at post-natal stages. We determined that Ofd1 plays a crucial role in forebrain development, and in particular in the control of dorso-ventral patterning and early corticogenesis. Interestingly, we observed abnormal activation of the Sonic hedgehog (Shh) and Planar Cell Polarity (PCP) signalling, two major pathways modulating brain development. Ultrastructural studies demonstrated that early Ofd1 inactivation results in the absence of ciliary axonemes despite the presence of mature basal bodies that are correctly orientated and docked. On the contrary, Ofd1 inducible-mediated inactivation at birth does not affect ciliogenesis in the cortex demonstrating for the first time a developmental stage-dependent role for a basal body protein in ciliogenesis. Moreover, we showed a defective cytoskeletal organization in Ofd1 null embryos, most likely due to lack of ciliary axonemes. Thus, the present study identifies Ofd1 as a developmental disease gene that is critical for forebrain development by regulating proper axoneme formation during ciliogenesis in embryonic life, and elucidates the precise step of ciliogenesis in which Ofd1 plays a crucial role in vivo.