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 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.

Probing disrupted neurodevelopment in autism using human stem cell‐derived neurons and organoids: An outlook into future diagnostics and drug development

“…239,240 KIDLIA is a neural-specific X-linked gene that is important for normal neuronal migration and dendritic outgrowth potentially through inhibition of RhoA activity. 234 TAOK2 encodes for a protein that participates in Sema3A/Neuropilin1 activity and helps regulate neurite outgrowth. 241 AUTS2, previously discussed for its role in neuronal migration, has also been shown to regulate neurite outgrowth, through the same Rac1-mediated pathway.…”

Functional roles of p120ctn family of proteins in central neurons

“…Knockdown of the nuclear protein KIDLIA, an X-linked autism protein, increases the total and surface levels of N-cadherin [54]. This leads to a sequestration of δ-catenin in the membrane pool resulting in decreased levels of free cytosolic δ-catenin [54].…”

“…Knockdown of the nuclear protein KIDLIA, an X-linked autism protein, increases the total and surface levels of N-cadherin [54]. This leads to a sequestration of δ-catenin in the membrane pool resulting in decreased levels of free cytosolic δ-catenin [54]. This increases activation of Rho which results in decreased actin mobility in the neurite growth cone that in turn inhibits neurite outgrowth and branching [54].…”

“…The grey regions indicate phosphorylation enriched regions before (region A) and after the ARM domains (region B) in each protein. Reference ID: 1, [30]; 2, [82]; 3, [27]; 4, [83]; 5, [84]; 6, [31]; 7, [53]; 8, combination of [29,54,75,81,85]; Ub, [87]; Palm: [19]. The reference protein sequences and region of the ARM repeats are as in Fig.…”

Loss of zebrafish ctnnd2b results in disorganised forebrain neuron clusters

“…During development of the nervous system, the encoded protein ∂ -catenin appears to be involved in various neurodevelopment processes. These include neuronal differentiation (Lee et al, 2016), synaptic dysfunction (Israely et al, 2004), dendritic branching, spine morphogenesis (Kim et al, 2008), and maintenance of mature dendrites and dendritic spines (Matter et al, 2009) (Gilbert and Man, 2016). Homozygous mice expressing the GFP-tagged N-terminal domain of CTNND2 show spatial learning difficulties and abnormal fear conditioning (Israely et al, 2004), possibly due to abnormalities in dendritic arbour maintenance (Matter et al, 2009), suggesting that loss of ∂ -catenin affects behaviour.…”