Cytolinker Gas2L1 regulates axon morphology through microtubule‐modulated actin stabilization

Abstract

Crosstalk between the actin and microtubule cytoskeletons underlies cellular morphogenesis. Interactions between actin filaments and microtubules are particularly important for establishing the complex polarized morphology of neurons. Here, we characterized the neuronal function of growth arrest‐specific 2‐like 1 (Gas2L1), a protein that can directly bind to actin, microtubules and microtubule plus‐end‐tracking end binding proteins. We found that Gas2L1 promotes axon branching, but restricts axon elongation in cultured rat hippocampal neurons. Using pull‐down experiments and in vitro reconstitution assays, in which purified Gas2L1 was combined with actin and dynamic microtubules, we demonstrated that Gas2L1 is autoinhibited. This autoinhibition is relieved by simultaneous binding to actin filaments and microtubules. In neurons, Gas2L1 primarily localizes to the actin cytoskeleton and functions as an actin stabilizer. The microtubule‐binding tail region of Gas2L1 directs its actin‐stabilizing activity towards the axon. We propose that Gas2L1 acts as an actin regulator, the function of which is spatially modulated by microtubules.

Huntington’s Disease—An Outlook on the Interplay of the HTT Protein, Microtubules and Actin Cytoskeletal Components

“…The interaction between actin and MTs by cross-linker proteins is very important for establishing the complex polarized morphology of neurons. During the formation of axons, actin filaments are indirectly stabilized by MTs [35], especially in the initial segment of axon, which is the unique neural compartment, playing a decisive role in generating the action potential and polarity of neurons [36]. Axon forms after neurite expansion due to the local stabilization of MTs in pre-axonal neurites [22].…”

“…MTs and their dynamic behavior affect not only the formation and functioning of neurons and a healthy brain but also the processes of brain aging and the development of neurodegenerative diseases [1,37]. Many neurological diseases arise due to defects in MTs and other components of the cytoskeleton and/or their regulation [1,35].…”

The actin regulator profilin 1 is functionally associated with the mammalian centrosome

“…The centrosome is the major microtubule-organizing structure in eukaryotic cells and as such crucial for intracellular architecture, cell polarity, and directional migration; consequently it has intrigued scientists for decades (1). Studies of the complex protein composition of mammalian centrosomes (2,3,4) combined with high-resolution imaging of centrosome behavior in cultured cells have led to the realization that in addition to being intimately linked with the microtubule system they are also closely connected to the actin microfilament system (2,5,6,7,8,9,10), reflecting the tight coordination and polarization of microtubule and actin organization (11,12,13). Several actin regulatory components such as WASH, Arp2/3, cofilin, and members of the formin family (2,7,14) have been found to be associated with the centrosome and likely to govern centrosome-linked actin reorganization.…”

Precursor types predict the stability of neuronal branches

“…The microtubule-binding proteins doublecortin (Fu et al, 2013) and Gas2L1 (Willige et al, 2019) regulate F-actin stability, altering axon branching. Reduction of Map7 induces more branch initiations while decreasing branch stability (Tymanskyj et al, 2017), which might be explained by inducing more lamellipodia branches or by separate effects on microtubule stability and precursor types.…”