Delta-Catenin as a Modulator of Rho GTPases in Neurons

Abstract

Small Rho GTPases are molecular switches that are involved in multiple processes including regulation of the actin cytoskeleton. These GTPases are activated (turned on) and inactivated (turned off) through various upstream effector molecules to carry out many cellular functions. One such upstream modulator of small Rho GTPase activity is delta-catenin, which is a protein in the p120-catenin subfamily that is enriched in the central nervous system. Delta-catenin affects small GTPase activity to assist in the developmental formation of dendrites and dendritic spines and to maintain them once they mature. As the dendritic arbor and spine density are crucial for synapse formation and plasticity, delta-catenin’s ability to modulate small Rho GTPases is necessary for proper learning and memory. Accordingly, the misregulation of delta-catenin and small Rho GTPases has been implicated in several neurological and non-neurological pathologies. While links between delta-catenin and small Rho GTPases have yet to be studied in many contexts, known associations include some cancers, Alzheimer’s disease (AD), Cri-du-chat syndrome, and autism spectrum disorder (ASD). Drawing from established studies and recent discoveries, this review explores how delta-catenin modulates small Rho GTPase activity. Future studies will likely elucidate how PDZ proteins that bind delta-catenin further influence small Rho GTPases, how delta-catenin may affect small GTPase activity at adherens junctions when bound to N-cadherin, mechanisms behind delta-catenin’s ability to modulate Rac1 and Cdc42, and delta-catenin’s ability to modulate small Rho GTPases in the context of diseases, such as cancer and AD.

p120-catenin subfamily members have distinct as well as shared effects on dendrite morphology during neuron development in vitro

“…p120-catenin has been shown to inhibit RhoA and activate Rac1 in multiple cell types, including neurons Noren et al, 2000;Grosheva et al, 2001;Elia et al, 2006). RhoA inhibition and Rac1 activation were established to increase dendritic arborization (Nakayama et al, 2000;Tashiro et al, 2000;Tashiro and Yuste, 2004;Guiler et al, 2021;Donta et al, 2022). Thus, our results…”

“…p120-catenin has been shown to inhibit RhoA and activate Rac1 in multiple cell types, including neurons ( Anastasiadis et al, 2000 ; Noren et al, 2000 ; Grosheva et al, 2001 ; Elia et al, 2006 ). RhoA inhibition and Rac1 activation were established to increase dendritic arborization ( Nakayama et al, 2000 ; Tashiro et al, 2000 ; Tashiro and Yuste, 2004 ; Guiler et al, 2021 ; Donta et al, 2022 ). Thus, our results are consistent with the hypothesis that p120-catenin expression increases dendritic arborization by inhibiting RhoA and activating Rac1, with the converse occurring upon p120-catenin depletion.…”

“…Morphological changes due to delta-catenin overexpression and knockdown are consistent with previous studies. There are multiple plausible mechanisms of how delta-catenin influences the dendritic arbor ( Donta et al, 2022 ). Delta-catenin has been shown to inhibit RhoA and activate Rac1 ( Martinez et al, 2003 ; Abu-Elneel et al, 2008 ; Kim et al, 2008 ; Gu et al, 2009 ; Gilbert and Man, 2016 ).…”

“…Finally, as abnormal dendrite morphology is seen in multiple neurological disorders like Alzheimer’s disease, schizophrenia, and autism spectrum disorder, determining the mechanisms of how each catenin modulates dendrite morphology may help point to new therapeutic approaches or considerations for these diseases. Interestingly, p120-subfamily catenins, most prominently delta, have associations with pathological states involving neurons and brain functions ( Xie et al, 2005 ; Nolze et al, 2013 ; Donta et al, 2022 ).…”

“…p120-catenin and delta-catenin have been found to regulate dendrite morphology in neurons through the cadherin-catenin complex and by modulating small Rho GTPase activity ( Elia et al, 2006 ; Arikkath et al, 2008 ; Kim et al, 2008 ; Edbauer et al, 2009 ; Donta et al, 2022 ). Depletion of p120-catenin and delta-catenin each result in decreased dendritic length and branching, while increasing delta-catenin expression increased dendritic length and branching in neurons ( Elia et al, 2006 ; Arikkath et al, 2008 ; Kim et al, 2008 ; Edbauer et al, 2009 ; Baumert et al, 2020 ).…”