δ-Catenin-induced Dendritic Morphogenesis

Abstract

␦-Catenin was first identified through its interaction withPresenilin-1 and has been implicated in the regulation of dendrogenesis and cognitive function. However, the molecular mechanisms by which ␦-catenin promotes dendritic morphogenesis were unclear. In this study, we demonstrated ␦-catenin interaction with p190RhoGEF, and the importance of Akt1-mediated phosphorylation at Thr-454 residue of ␦-catenin in this interaction. We have also found that ␦-catenin overexpression decreased the binding between p190RhoGEF and RhoA, and significantly lowered the levels of GTP-RhoA but not those of GTP-Rac1 and -Cdc42. ␦-Catenin T454A, a defective form in p190RhoGEF binding, did not decrease the binding between p190RhoGEF and RhoA. ␦-Catenin T454A also did not lower GTP-RhoA levels and failed to induce dendrite-like process formation in NIH 3T3 fibroblasts. Furthermore, ␦-catenin T454A significantly reduced the length and number of mature mushroom shaped spines in primary hippocampal neurons. These results highlight signaling events in the regulation of ␦-catenininduced dendrogenesis and spine morphogenesis.␦-Catenin was first identified by yeast two-hybrid screening as a molecule that interacts with Presenilin-1 (PS-1), 3 which is the most prominently mutated gene in familial Alzheimer disease (FAD) patients (1, 2). The interaction of ␦-catenin with PS-1, along with its abundant expression in neurons, suggests that ␦-catenin has specialized neuronal functions (3, 4). Indeed, ␦-catenin-deficient mice showed severe learning deficits and abnormal synaptic plasticity, suggesting a special role of ␦-catenin at the synapse (5). Furthermore, the hemizygous loss of the chromosomal 5p15.2 region, which contains the human ␦-catenin gene, results in the severe mental retardation associated with Cri du Chat syndrome. This chromosomal abnormality may account for 1% of all mentally retarded individuals (6).Structural analysis indicated that ␦-catenin is a member of the p120-Catenin (hereafter, p120 ctn ) subfamily of armadillo proteins and has a DSWV sequence at the C terminus that binds to the PDZ (PSD-95/Disc-larg/ZO-1) domain-containing proteins (7). ␦-Catenin also contains SH3 binding domains at the N terminus (4, 8), a GKKKKKKK sequence (putative NLS) that can potentially promote lipid intermixing (9), and a proline-rich domain that is likely to be involved in the interaction with the actin-binding protein, Profilin (4). The presence of 10 Arm repeats in ␦-catenin suggests its potential participation in various protein-protein interactions. In addition to PS-1, the ␦-catenin-associated proteins identified thus far include E-cadherin (4), S-SCAM (7), p0071 (10), Densin-180 (11), PSD-95, Abl (8), Cortactin (12), sphingosine kinase (13), and Kaiso (14), suggesting its many possible roles in cells. Our previous reports demonstrated that the overexpression of ␦-catenin induces the branching of dendrite-like processes in both NIH 3T3 fibroblasts and primary hippocampal neurons (15). We have also reported that an E18 hippocampal neuron ...

A δ-Catenin Signaling Pathway Leading to Dendritic Protrusions

“…RhoA inhibits, whereas Rac and Cdc42 promote, the growth and/or stability of dendritic spines. Consistent with the cellular phenotype induced by ␦-catenin, expression of ␦-catenin inhibits RhoA (8) by decreasing the binding between p190RhoGEF and RhoA, resulting in lower levels of GTP-RhoA (17). A similar mechanism of RhoA inhibition may operate via p120 ctn (43)(44)(45) in its role in organizing actin into filaments.…”

“…1). As shown previously (8,17,33), ␦-catenin dramatically induced protrusions. Neurons were transfected with either GFP alone or full-length GFP-␦-catenin and analyzed for the number of protrusions at 20 DIV based on GFP visualization, ␦-catenin, and PSD95 immunolocalization (Fig.…”

“…7). Recently, phosphorylation at Thr-454 was shown to sequester p190RhoGEF (17). However, a tryptic peptide containing Thr-454 was recovered and was constitutively phosphorylated on Ser-457 or Ser-458, but not on Thr-454, indicating that DHPG did not induce a detectable phosphorylation at this site (supplemental Table SII).…”

“…These are Erbin (14) and Densin-180 (15), which interacts with the metabotropic glutamate receptor scaffold protein Shank (16). ␦-Catenin interacts with p190RhoGEF through AKT1-mediated phosphorylation, indicating an additional essential role for ␦-catenin in dendritic morphogenesis (17). This complex set of interaction partners suggests that ␦-catenin is pivotally positioned to coordinate synaptic activity with cell-cell adhesion properties.…”

Determination of C-Terminal <I>δ</I>-Catenin Responsible for Inducing Dendritic Morphogenesis

“…18 27 These results suggest that 1040-1247 amino acid of -catenin have crucial role in inducing dendrogenesis yet not be fully understood.…”