Species-specific imprinting of Adam23 and its implications for gyrencephalic brain development

Abstract

Genomic imprinting is a parent-of-origin-specific epigenetic mechanism with essential roles in placental development and fetal growth in mice, but its contribution to brain function and evolution remains unclear. Here, we investigated genomic imprinting in the ferret, a gyrencephalic mammal whose cortical architecture closely resembles that of humans rather than mice. Guided by human imprinting datasets, we screened 65 candidate genes in ferret brain and identified paternal expression of Adam23, maternal expression of Atp10a, and biallelic expression of genes including Pxdc1, Wrb and Ube3a. Adam23 showed paternal expression in ferret cortex, particularly in the occipital region, whereas it was biallelically expressed in mouse brain. In human SH-SY5Y cells, ADAM23 was biallelic in undifferentiated cells but shifted toward monoallelic expression upon neuronal differentiation. CpG analysis of upstream islands indicated that Adam23 imprinting in ferrets is independent of promoter methylation, suggesting a non-canonical mechanism. Functional assays in Neuro-2aTG cells showed that Adam23 knockdown enhances neurite outgrowth, whereas overexpression promotes cell proliferation. These findings identify Adam23 as a non-canonical imprinted gene whose dosage influences stem cell dynamics and neurite development, linking imprinting to the evolution of gyrencephalic cortical structures and highlighting the ferret as a valuable model for imprinting studies in higher-order brain function.