TY - JOUR T1 - The X-Linked Autism Protein KIAA2022/KIDLIA Regulates Neurite Outgrowth via N-Cadherin and δ-Catenin Signaling JF - eneuro JO - eNeuro DO - 10.1523/ENEURO.0238-16.2016 VL - 3 IS - 5 SP - ENEURO.0238-16.2016 AU - James Gilbert AU - Heng-Ye Man Y1 - 2016/09/01 UR - http://www.eneuro.org/content/3/5/ENEURO.0238-16.2016.abstract N2 - 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 found that KIDLIA is distributed exclusively in the nucleus. In the developing rat brain, it is expressed only in the cortical plate and subplate region but not in the intermediate or ventricular zone. Using in utero electroporation, we found that short hairpin RNA (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 suppression of dendritic growth and branching. At the molecular level, we found that KIDLIA suppression leads to an increase in cell-surface N-cadherin and an elevated association of N-cadherin with δ-catenin, resulting in 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, overexpression 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. ER -