The C. elegans homolog of human panic-disorder risk gene TMEM132D orchestrates neuronal morphogenesis through the WAVE-regulatory complex

Abstract

TMEM132D is a human gene identified with multiple risk alleles for panic disorders, anxiety and major depressive disorders. Defining a conserved family of transmembrane proteins, TMEM132D and its homologs are still of unknown molecular functions. By generating loss-of-function mutants of the sole TMEM132 ortholog in C. elegans, we identify abnormal morphologic phenotypes in the dopaminergic PDE neurons. Using a yeast two-hybrid screen, we find that NAP1 directly interacts with the cytoplasmic domain of human TMEM132D, and mutations in C. elegans tmem-132 that disrupt interaction with NAP1 cause similar morphologic defects in the PDE neurons. NAP1 is a component of the WAVE regulatory complex (WRC) that controls F-actin cytoskeletal dynamics. Decreasing activity of WRC rescues the PDE defects in tmem-132 mutants, whereas gain-of-function of TMEM132D in mammalian cells inhibits WRC, leading to decreased abundance of select WRC components, impaired actin nucleation and cell motility. We propose that metazoan TMEM132 family proteins play evolutionarily conserved roles in regulating NAP1 protein homologs to restrict inappropriate WRC activity, cytoskeletal and morphologic changes in the cell.

Lnc-TMEM132D-AS1 as a potential therapeutic target for acquired resistance to osimertinib in non-small-cell lung cancer

“…TMEM132D is a human gene identified with multiple risk alleles for panic disorders, anxiety and major depressive disorders, but its actual role is yet not fully understood. 34 Here, we present the first study investigating the function of lnc-TMEM132D-AS1 in acquired resistance to osimertinib in NSCLC. We identified that lnc-TMEM132D-AS1 was significantly upregulated in NSCLC cell lines and in the plasma of patients with acquired resistance to osimertinib.…”

“…TMEM132D is a human gene identified with multiple risk alleles for panic disorders, anxiety and major depressive disorders, but its actual role is yet not fully understood. 34…”

The intrinsically disordered cytoplasmic tail of a dendrite branching receptor uses two distinct mechanisms to regulate the actin cytoskeleton

“…Many neuronal receptors, including SYG-1, Robo, Neogenin, TMEM132, neuroligins, and various protocadherins, contain a short WIRS peptide motif in their ICD, which allows them to recruit the WRC to their sites of action at membranes to regulate local actin polymerization in diverse cellular processes (Chaudhari et al, 2021; Chia et al, 2014; Fan et al, 2018; Lee et al, 2016; Wang et al, 2021; Xing et al, 2018). The HPO-30 ICD does not contain a WIRS motif.…”

“…These ligands include small GTPases (e.g., Rac1 and Arf), acidic phospholipids (e.g., PIP3), various adaptor proteins, and over 100 different membrane proteins that contain a 6 amino acid peptide motif named the WIRS motif (WRC interacting receptor sequence, defined as F-x-T/S-F-x-x, where F is a bulky hydrophobic residue and x is any residues) (Chen et al, 2017(Chen et al, , 2014a(Chen et al, , 2010aEden et al, 2002;Kobayashi et al, 1998;Koronakis et al, 2011;Lebensohn and Kirschner, 2009;Rottner et al, 2021). Many WIRS-containing membrane proteins, such as SYG-1, Robo, Neogenin, TMEM132, neuroligins, and various protocadherins, are important neuronal receptors and have been shown to rely on the WIRS-WRC interaction to regulate various processes in neural development (Chaudhari et al, 2021;Chia et al, 2014;Fan et al, 2018;Lee et al, 2016;Wang et al, 2021;Xing et al, 2018).…”

Differential expression of the Tmem132 family genes in the developing mouse nervous system

“…TMEM132 proteins all contain extracellular Ig domains and intracellular WAVE complex binding domains, suggesting that they may mediate cell-cell interaction and intracellular actin network organization (Sanchez-Pulido and Ponting, 2018). Consistent with this notion, the loss of nematode Tmem132 led to abnormal neurite projection (Wang et al, 2021). The Drosophila Tmem132 homolog, dtn, was involved in reproduction and nociception, but the exact cellular mechanism was not revealed (Chon et al, 2021;Honjo et al, 2016).…”