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

AbstractNeurodevelopmental 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.Author SummaryThe mammalian brain, seat of cognitive and behavioral processing, is the result of numerous, complex but coordinated mechanisms of development such as cell proliferation, migration, neuritogenesis, synaptogenesis and neural network formation. Patients with disruptions in these fundamental processes will typically exhibit neurodevelopmental disorders. As such, the rare Verheij syndrome is a condition where patients display some neurological features such as microcephaly (dramatic reduction in brain cortical size) or agenesis of the corpus callosum (loss of the main commissure between hemispheres). The human gene SCRIB is included within a region, identified as 8q24.3, which is deleted in patients with this syndrome. In this paper, we generated mouse models to assess the consequences of selective genetic inactivation of Scrib on the brain architecture and function. From the neuroanatomical standpoint, we show that Scrib controls the formation of the cerebral cortex and the corpus callosum. This is correlated with behavioral deficits such as disrupted locomotion, learning and memory. Altogether, this work validates the association between Scrib loss and the brain-associated clinical features observed in individuals with Verheij/8q24.3 deletion syndrome.

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