DCXknockout ferret reveals a neurogenic mechanism in cortical development

Abstract

SUMMARYDoublecortin (DCX) is one of the major causal proteins leading to lissencephaly and subcortical band heterotopia in human patients. However, our understanding of this disease, as well as the function of DCX during neurogenesis, remains limited due to the absence of suitable animal models that accurately represent human phenotypes. Here, we conducted a comprehensive examination of the neocortex at different stages inDCXknockout ferrets. We corroborated the neurogenic functions ofDCXin progenitors. Loss of function of DCX led to the over-proliferation of neural progenitors and the truncation of basal processes of radial glial cells, which contributed to the thickening of cortices and the stalling of neurons underneath the cortical plate during neurogenic stages, respectively. We also present the first-ever cell atlas of the lissencephaly disease model, which embraces an almost reversed neuronal lamination distribution in the neocortex compared to the normal controls. Furthermore, we discovered alterations in molecular signatures tied to epilepsy, a condition frequently observed in lissencephaly patients. We also provided compelling evidence that the distribution of GABAergic inhibitory neurons in the cortex is intricately linked to glutamatergic excitatory neurons in a subtype-specific manner. In conclusion, our research offers new insights to expand our understanding of DCX’s functions and enrich our comprehension of lissencephaly’s intricacies.HighlightsDCXferrets phenocopy human lissencephaly and subcortical band heterotopia syndromeDCXis required for NPC proliferation and radial glial basal fiber extensionThe atlas of lissencephalic cortex is illustrated using snRNA-seq and spatial transcriptomeInhibitory neurons couple to excitatory neurons in a cell-type specific manner