16-P024 Functional characterization of the ciliary proteins lebercilin and MKS1

hemizygous male mutants die by E12 and display neural tube defects, exencephaly and left–right asymmetry. Analysis of heterozygous female mutants revealed a severe brain phenotype including expansion of the ventral telencephalon in the dorsal part of the brain, reduction of the cortex and defects in the formation of dorsomedial telencephalic structures from E12.5. Morphological staining of mutant brains showed disorganization of brain architecture with a progressive disappearance of the olfactory bulbs. In situ hybridization revealed ectopic expression of transcription factors critical for development of ventral telencephalon including Nkx2.6, Dlx2, Mash, Gsh2 while markers strongly expressed in the dorsal cortex, such as Ngn2 and Pax6, displayed a normal pattern of expression. Defective brain patterning was found associated with abnormal Shh signaling and impairment of the processing of Gli3. In addition, we observed an upregulation of canonical Wnt signaling in the cortex and the caudal forebrain. Preliminary data also revealed cilia abnormalities within affected structures of the CNS. Altogether, these data indicate that Ofd1 is a patterning factor essential for development and specification of the telencephalon. Ongoing studies will clarify the contribution of cilia to the CNS defects observed in these mutants and the molecular basis of the brain abnormalities observed in OFDI syndrome.