Early loss of Scribble affects cortical development and interhemispheric connectivity resulting in psychomotor dysregulation

Neurodevelopmental disorders arise from combined defects in processes including cell proliferation, differentiation, migration and commissure formation. The evolutionarily conserved tumor-suppressor protein Scribble (Scrib) serves as a nexus to transduce signals for the establishment of apicobasal and planar cell polarity during these processes. Human SCRIB gene mutations are associated with neural tube defects and this gene is located in the minimal critical region deleted in the rare Verheij syndrome. In this study, we generated brain-specific conditional cKO mouse mutants and assessed the impact of the Scrib deletion on brain morphogenesis and behavior. We showed that embryonic deletion of Scrib in the telencephalon leads to cortical thickness reduction (microcephaly) and alteration of interhemispheric connectivity (corpus callosum and hippocampal commissure agenesis). We correlated these phenotypes with the identification of novel roles for Scrib , both cell- and non-cell-autonomous, on neuronal migration and axonal guidance respectively. Finally, we show that Scrib cKO mice have psychomotor deficits such as locomotor activity impairment and memory alterations. Altogether, we show that Scrib is essential for early brain development and that the outcomes of its brain-specific disruption support a direct or indirect participation of Scrib to neurodevelopmental pathologies.