Actin regulation by tropomodulin and tropomyosin in neuronal morphogenesis and function

Abstract

Actin is a profoundly influential protein; it impacts, among other processes, membrane morphology, cellular motility, and vesicle transport. Actin can polymerize into long filaments that push on membranes and provide support for intracellular transport. Actin filaments have polar ends: the fast-growing (barbed) end and the slow-growing (pointed) end. Depolymerization from the pointed end supplies monomers for further polymerization at the barbed end. Tropomodulins (Tmods) cap pointed ends by binding onto actin and tropomyosins (Tpms). Tmods and Tpms have been shown to regulate many cellular processes; however, very few studies have investigated their joint role in the nervous system. Recent data directly indicate that they can modulate neuronal morphology. Additional studies suggest that Tmod and Tpm impact molecular processes influential in synaptic signaling. To facilitate future research regarding their joint role in actin regulation in the nervous system, we will comprehensively discuss Tpm and Tmod and their known functions within molecular systems that influence neuronal development.

Tmod2 is a regulator of cocaine responses through control of striatal and cortical excitability, and drug-induced plasticity

“…Operant learning is a form of associative learning that is dependent on various brain regions including nucleus accumbens and hippocampus 112,113 . Since Tmod2 is an actin-regulator 88 , mutants were tested for structural anomalies of the brain using MRI.…”

“…Since TMOD2 regulates dendritic arborization 39,88 , synapse density and maturation, and synaptic plasticity 39,40,89 , we hypothesized that the firing properties of neurons might be modified due to altered synaptic connectivity. To test this, we harvested cortical cells from P0-P1 pups and quantified the spontaneous firing features of cultured neurons on MEA plates.…”

Multifunctional roles of Tropomodulin-3 in regulating actin dynamics

“…However, the nanomolar affinity of Tmod3 for Tpm-F-actin pointed ends implies that the amount of cytosolic Tmod3 available to bind monomers and influence the monomer pool would be limited by the numbers of Tpm-F-actin pointed ends in cells, which has not been determined. Future studies of actin dynamics and F-actin network structure in lamellipodia of cells expressing Tmod mutants with disabled monomer binding, Factin capping, or Tpm binding sites (Colpan et al 2013;Gray et al 2017;Yamashiro et al 2012) are required to reveal the mechanistic details of Tmod3 regulation of F-actin network assembly in lamellipodia protrusion and cell migration.…”

“…In this review, we highlight the function of Tmods in the diverse F-actin networks of nonmuscle cells. The developmental expression and cellular functions of Tmod1, 2, and 4 isoforms have been reviewed elsewhere (Fowler and Dominguez 2017;Gokhin and Fowler 2011c;Gokhin and Fowler 2013;Gray et al 2017;Yamashiro et al 2012) and will not be discussed in great detail. Rather, here we focus on the role(s) of Tmod3.…”

Tropomodulin Isoform-Specific Regulation of Dendrite Development and Synapse Formation

“…By blocking monomer exchange at filament ends and inhibiting filament elongation or depolymerization, Tmod regulates the stability, length, and architecture of complex actin networks in diverse cell types (Yamashiro et al, 2012). Of the four Tmod isoforms, Tmod1, Tmod2, and Tmod3 are expressed in the CNS (Sussman et al, 1994;Watakabe et al, 1996;Conley et al, 2001;Cox et al, 2003). Tmod1 is expressed in many types of terminally differentiated cells (including neurons), Tmod2 is expressed solely in neurons, and Tmod3 is ubiquitously expressed (Yamashiro et al, 2012).…”