Formin 2 regulates the stabilization of filopodial tip adhesions in growth cones and affects neuronal outgrowth and pathfinding in vivo

Abstract

Growth cone filopodia are actin-based mechanosensory structures that are essential for chemoreception and the generation of contractile forces necessary for directional motility. However, little is known about the influence of filopodial actin structures on substrate adhesion and filopodial contractility. Formin 2 (Fmn2) localizes along filopodial actin bundles and its depletion does not affect filopodia initiation or elongation. However, Fmn2 activity is required for filopodial tip adhesion maturation and the ability of filopodia to generate traction forces. Dysregulation of filopodia in Fmn2-depleted neurons leads to compromised growth cone motility. Additionally, in mouse fibroblasts, Fmn2 regulates ventral stress fiber assembly and affects the stability of focal adhesions. In the developing chick spinal cord, Fmn2 activity is required cellautonomously for the outgrowth and pathfinding of spinal commissural neurons. Our results reveal an unanticipated function for Fmn2 in neural development. Fmn2 regulates structurally diverse bundled actin structures, parallel filopodial bundles in growth cones and anti-parallel stress fibers in fibroblasts, in turn modulating the stability of substrate adhesions. We propose Fmn2 as a mediator of actin bundle integrity, enabling efficient force transmission to the adhesion sites.

Formin 2 links neuropsychiatric phenotypes at young age to an increased risk for dementia

“…While the precise mechanisms that couple FMN2‐mediated defects in hippocampal function to deregulation of gene expression are likely multifactorial, it is interesting to note that stimuli which promote rearrangement of the actin cytoskeleton were found to induce gene expression changes (Olson & Nordheim, ). In line with this, we observe that loss of FMN2 affects actin dynamics which confirms previous data from other cellular systems (Pfender et al , ; Schuh, ; Montaville et al , ; Sahasrabudhe et al , ) and is in agreement with the fact that blocking actin dynamics in the hippocampus impairs fear extinction (Fischer et al , ). Alteration of actin dynamics has been associated with ERK1/2‐mediated changes in gene expression (Wang & Hatton, ; Berti & Seger, ).…”

The formin Fmn2 is required for the development of an excitatory interneuron module in the zebrafish acoustic startle circuit

“…In line with previous studies showing the expression of Fmn2 in the nervous system of human, mice (Leader and Leder, 2000), and chick (Sahasrabudhe et al, 2016), Fmn2 mRNA is also enriched in the zebrafish nervous system.…”

“…A study comparing expression patterns of the formin-like (fmnl) subfamily of formins shows that the formins, fmnl1a, fmnl1b, fmnl2a, fmnl2b and fmnl3 are expressed in the nervous system in a dynamic temporal manner during development, in addition to expression in non-neuronal tissues (Santos-Ledo et al, 2013). However, the role of formins in the development of neural circuits in zebrafish is not well explored despite several studies reporting the enrichment of formins in vertebrate nervous systems (Leader and Leder, 2000;Krainer et al, 2013;Dutta and Maiti, 2015;Sahasrabudhe et al, 2016). The only report available implicates the formin Daam1a in the asymmetric morphogenesis of the zebrafish habenula and the regulation of the dendritic and axonal processes of the dorsal habenular neurons (Colombo et al, 2013).…”

“…Most formins are broadly expressed in multiple tissues types (Schönichen and Geyer, 2010;Breitsprecher and Goode, 2013;Krainer et al, 2013;Dutta and Maiti, 2015; Kawabata Galbraith and Kengaku, 2019) but the non-diaphanous related formin, , is found to be enriched in the developing and the mature nervous systems of mice, humans and chicken (Leader and Leder, 2000;Katoh and Katoh, 2004;Dutta and Maiti, 2015;Sahasrabudhe et al, 2015). Fmn2 has been implicated in neurodevelopmental disorders, intellectual disability, age-related dementia, microcephaly and sensory processing dysfunction in humans (Perrone et al, 2012;Almuqbil et al, 2013;Law et al, 2014;Agís-Balboa et al, 2017;Anazi et al, 2017;Marco et al, 2018).…”

“…Fmn2 is required for growth cone motility and axonal pathfinding of spinal neurons. Filopodial stability and the dynamics of the adhesion complexes between the growth cone and the substrate are regulated by Fmn2 (Sahasrabudhe et al, 2016;Ghate et al, 2020). Another study has identified actinmicrotubule crosstalk mediated by Fmn2 as a mechanism underlying growth cone turning (Kundu et al, 2020).…”