Tropomodulin isoforms utilize specific binding functions to modulate dendrite development

Abstract

Tropomodulins (Tmods) cap F-actin pointed ends and have altered expression in the brain in neurological diseases. The function of Tmods in neurons has been poorly studied and their role in neurological diseases is entirely unknown. In this paper we show that Tmod1 and Tmod2, but not Tmod3, are positive regulators of dendritic complexity and dendritic spine morphology. Tmod1 increases dendritic branching distal from the cell body and the number of filopodia/thin spines. Tmod2 increases dendritic branching proximal to the cell body and the number of mature dendritic spines. Tmods utilize two actin-binding sites and two tropomyosin (Tpm)-binding sites to cap F-actin. Overexpression of Tmods with disrupted Tpm-binding sites indicates that Tmod1 and Tmod2 differentially utilize their Tpm- and actin-binding sites to affect morphology. Disruption of Tmod1’s Tpm-binding sites abolished the overexpression phenotype. In contrast, overexpression of the mutated Tmod2 caused the same phenotype as wild type overexpression. Proximity ligation assays indicate that the mutated Tmods are shuttled similarly to wild type Tmods. Our data begins to uncover the roles of Tmods in neural development and the mechanism by which Tmods alter neural morphology. These observations in combination with altered Tmod expression found in several neurological diseases also suggest that dysregulation of Tmod expression may be involved in the pathology of these diseases.

Actin regulation by tropomodulin and tropomyosin in neuronal morphogenesis and function

“…This pathway regulated motility and altered cell shape, which are known to be altered by changes in Tmod expression (Fath et al, 2011; Fischer et al, 2003; Guillaud et al, 2014; Moroz et al, 2013a). We have shown that overexpression of Tmod1 increases the complexity of the dendritic arbor (Gray et al, 2016). These two observations suggest that upregulation of Tmod1 via wnt signaling could be a mechanism by which the brain may signal to increase dendritic complexity.…”

“…While Tpms and Tmods are intimately related at the pointed ends of actin filaments, only one paper has studied the importance of their interaction in neurons (Gray et al, 2016). Here we will explore the known roles of Tpms and Tmods on the formation of growth cones, dendrites, dendritic spines, and axons.…”

“…Although a detailed study on the subcellular interaction between Tmods and Tpms in the growth cones is still lacking, recent findings suggest a close interaction between Tpms and Tmods in growth cones (Gray et al, 2016). Proximity ligation assays (Figure 2) indicated proximity between exogenously expressed Tmod1 and Tmod2 with the endogenous Tpm3.1/Tpm3.2 in growth cones of developing hippocampal neurons (Gray et al, 2016).…”

“…Proximity ligation assays (Figure 2) indicated proximity between exogenously expressed Tmod1 and Tmod2 with the endogenous Tpm3.1/Tpm3.2 in growth cones of developing hippocampal neurons (Gray et al, 2016). …”

S100A10 identified in a genome-wide gene × cannabis dependence interaction analysis of risky sexual behaviours

“…48 A recent study demonstrated that TMOD2 is a positive regulator of dendritic complexity and spine morphology. 49 Cannabis use is well known to have a significant impact on brain structures that are enriched with cannabinoid receptors. 50 Although no other studies have verified this hypothesis yet (to date we can identify only 13 articles regarding TMOD2 function), we speculate that TMOD2 could be involved in the remodelling processes induced by cannabis use in brain areas relevant to sexual function and behaviours.…”