KCNQ1 regulates human neuronal development through mitochondrial and insulin signalling pathways

Abstract

KCNQ1 encodes a voltage-gated potassium channel implicated in various peripheral and neurological disorders, yet its role during human neuronal development remains unclear. To investigate this, we generated KCNQ1 knockouts (KO) in human induced pluripotent stem cell lines and differentiated them into neural stem cells (NSCs) and cortical neurons. KCNQ1-deficient NSCs showed impaired neurite outgrowth, linked to reduced cell adhesion and disrupted neural cell adhesion molecule (NCAM) signalling. This phenotype was reproduced in wild-type and heterozygous lines by pharmacological KCNQ1 inhibition. Whole transcriptome, proteome, and follow-up analyses revealed mitochondrial dysfunction in KO NSCs, including reduced mitochondrial copy number and ATP synthase expression. Additionally, evidence was obtained for an impairment of insulin signalling in NSCs and neurons, with diminished insulin receptor gene expression and perturbation of key downstream signalling pathways (RAS-MAPK, PI3K-AKT). In neurons, KCNQ1 loss resulted in decreased synaptic activity and a more immature gene expression profile. Overall, our work reveals a novel role for KCNQ1 in human neurodevelopment by regulating cell adhesion, mitochondrial function, and insulin signalling. This work increases our understanding of KCNQ1 function in neurons and its contribution to neurological phenotypes observed in patients with KCNQ1-related diseases.