Selective neurodevelopmental and behavioral deficits in Scrib conditional knock-out mice recapitulate some phenotypes associated with the Verheij/8q23.4 deletion syndrome.

Neurodevelopmental disorders often arise from combined defects in processes including cell proliferation, differentiation, neuronal migration, axonal pathfinding and commissure formation. Cell polarity proteins serve as a nexus to transduce signals for the establishment of these essential processes. Scribble (Scrib) is an evolutionarily conserved polarity protein that is known to regulate the establishment of apicobasal and planar cell polarity . Mutations in the human SCRIB gene are associated with neural tube defects and this gene is located in the minimal critical region deleted in the rare Verheij/8q24.3 deletion syndrome. In the present study, we evaluated the contribution of Scrib to some of the neurological features found in patients with this syndrome, including microcephaly and corpus callosum agenesis. Using various brain-specific conditional mouse mutants and in utero electroporation experiments, we assessed the impact of the spatio-temporal selective Scrib deletion on brain morphogenesis and animal behavior. Our results showed that global embryonic deletion of Scrib in the telencephalon lead to a reduction of cortical thickness and an alteration of interhemispheric connectivity. In addition, we identified cell-autonomous effects of Scrib on neuronal migration, and we suggest a non-cell-autonomous effect in axonal guidance. Finally, comparative behavioral analysis showed that mice with Scrib invalidation have psychomotor deficits. Altogether, our mouse models recapitulate a number of the phenotypes associated with Verheij/8q24.3 deletion syndrome patients, supporting the possibility that Scrib contributes to this rare disease.