The X-linked autism protein KIAA2022/KIDLIA regulates neurite outgrowth via N-cadherin and δ-catenin signaling

Abstract

Our previous work showed that loss of the KIAA2022 gene protein results in intellectual disability with language impairment and autistic behavior (KIDLIA, also referred to as XPN). However, the cellular and molecular alterations resulting from a loss-of-function of KIDLIA and its role in autism with severe intellectual disability remain unknown. Here we show that KIDLIA plays a key role in neuron migration and morphogenesis. We find that KIDLIA is distributed exclusively in the nucleus. In the developing rat brain, it is expressed only in the cortical plate and sublate region but not in the intermediate or ventricular zone. Using in utero electroporation, we find that shRNA-mediated knockdown of KIDLIA leads to altered neuron migration and a reduction in dendritic growth and disorganized apical dendrite projections in layer II/III mouse cortical neurons. Consistent with this, in cultured rat neurons, a loss of KIDLIA expression also leads to a suppression in dendritic growth and branching. At the molecular level, we find that KIDLIA suppression leads to an increase in cell-surface N-cadherin and an elevated association of N-cadherin with δ-catenin, resulting in a depletion of free δ-catenin in the cytosolic compartment. The reduced availability of cytosolic δ-catenin leads to elevated RhoA activity and reduced actin dynamics at the dendritic growth cone. Furthermore, in neurons with KIDLIA knockdown, over-expression of δ-catenin or inhibition of RhoA rescues actin dynamics, dendritic growth and branching. These findings provide the first evidence on the role of the novel protein KIDLIA in neurodevelopment and autism with severe intellectual disability.

Significance Statement: Autism spectrum disorder (ASD) is a neurodevelopmental impairment with a strong genetic basis. The cellular and molecular mechanisms linking the autism and intellectual disabillity -related genes to the impairment in brain development remain to be fully elucidated. This is the first study to examine the distribution, expression and neurobiological function of KIAA2022/KIDLIA, a novel gene protein implicated in ASD and intellectual disability. We report that KIDLIA is a neuron-specific nuclear protein expressed in the subplate and cortical plate in the developing brain. Loss of KIDLIA expression impairs neuron migration, dendritic growth and morphogenesis via regulation of the N-cadherin-δ-catenin signaling pathway and actin dynamics.