Profilin 1 delivery tunes cytoskeletal dynamics toward CNS axon regeneration

Pinto‐Costa, Rita; Sousa, Sara; Leite, Sérgio Carvalho; Nogueira‐Rodrigues, Joana; Silva, Tiago Ferreira da; Machado, Diana; Marques, Joana Beatriz Moreira; Costa, Ana; Liz, Márcia A.; Bartolini, Francesca; Brites, Pedro; Costell, Mercedes; Fässler, Reinhard; Sousa, Mónica Mendes

doi:10.1172/jci125771

Cited by 40 publications

(25 citation statements)

References 67 publications

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“…In neuronal cells, PFN1 mediates the opposite effect: The velocity of growing microtubules is threefold increased in PFN1-overexpressing N2A neuroblastoma cells (Henty-Ridilla et al, 2017). Increased PFN1 levels promote axon growth and regeneration of neurons in cell culture and in vivo by accelerating microtubule growth, while depletion of PFN1 curbs these processes (Pinto-Costa et al, 2020). These findings are in line with in vitro assays showing the direct enhancement of microtubule growth by PFN1 (Henty-Ridilla et al, 2017).…”

Section: Profilin 1 Vs Profilin 2a -From Proteins Mice and Chickensupporting

confidence: 73%

“…These findings are in line with in vitro assays showing the direct enhancement of microtubule growth by PFN1 (Henty-Ridilla et al, 2017). In addition, PFN1 coordinates microtubules with actin filaments in axons via formins (Pinto-Costa et al, 2020), which serve as a link between both filament systems (see for review Breitsprecher and Goode, 2013). In summary, PFN1 specifically balances microtubule dynamics in yet to be determined cellular settings and via so far unknown molecular mechanisms.…”

Section: Profilin 1 Vs Profilin 2a -From Proteins Mice and Chickensupporting

confidence: 70%

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Profilin Isoforms in Health and Disease – All the Same but Different

Murk

Ornaghi

Schiweck

2021

Front. Cell Dev. Biol.

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Profilins are small actin binding proteins, which are structurally conserved throughout evolution. They are probably best known to promote and direct actin polymerization. However, they also participate in numerous cell biological processes beyond the roles typically ascribed to the actin cytoskeleton. Moreover, most complex organisms express several profilin isoforms. Their cellular functions are far from being understood, whereas a growing number of publications indicate that profilin isoforms are involved in the pathogenesis of various diseases. In this review, we will provide an overview of the profilin family and “typical” profilin properties including the control of actin dynamics. We will then discuss the profilin isoforms of higher animals in detail. In terms of cellular functions, we will focus on the role of Profilin 1 (PFN1) and Profilin 2a (PFN2a), which are co-expressed in the central nervous system. Finally, we will discuss recent findings that link PFN1 and PFN2a to neurological diseases, such as amyotrophic lateral sclerosis (ALS), Fragile X syndrome (FXS), Huntington’s disease and spinal muscular atrophy (SMA).

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Section: Profilin 1 Vs Profilin 2a -From Proteins Mice and Chickensupporting

confidence: 73%

Section: Profilin 1 Vs Profilin 2a -From Proteins Mice and Chickensupporting

confidence: 70%

Profilin Isoforms in Health and Disease – All the Same but Different

Murk

Ornaghi

Schiweck

2021

Front. Cell Dev. Biol.

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“…The inhibition of actin assembly by profilin is a well characterized facet of profilin-based actin regulation in vitro. However, lipid-based or formin-mediated actin assembly mechanisms stimulated by profilin dominate cellular actin dynamics to maintain neuronal homeostasis, cellular morphologies, and signal transduction (Figure 6A)(Pimm et al, 2020; Pinto-Costa et al, 2020; Rotty et al, 2015; Skruber et al, 2018; Suarez et al, 2015; Zimmermann et al, 2017). Here we demonstrate that half of the identified ALS-associated profilin variants are impaired in formin-mediated actin assembly.…”

Section: Discussionmentioning

confidence: 99%

Biochemical characterization of actin assembly mechanisms with ALS-associated profilin variants

Liu¹,

Pimm²,

Haarer³

et al. 2022

Preprint

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Eight separate mutations in the actin-binding protein profilin-1 have been identified as a rare cause of amyotrophic lateral sclerosis (ALS). Profilin is essential for many neuronal cell processes through its regulation of lipids, nuclear signals, and cytoskeletal dynamics, including actin filament assembly. Direct interactions between profilin and actin monomers inhibit actin filament polymerization. In contrast, profilin can also stimulate polymerization by simultaneously binding actin monomers and proline-rich tracts found in other proteins. Whether the ALS-associated mutations in profilin compromise these actin assembly functions is unclear. We performed a quantitative biochemical comparison of the direct and formin-mediated impact for the eight ALS-associated profilin variants on actin assembly using classic protein-binding and single-filament microscopy assays. We determined that the binding constants of each profilin for actin monomers generally correlates with the actin nucleation strength associated with each ALS-related profilin. In the presence of formin, the A20T, R136W, Q139L, and C71G variants failed to activate the elongation phase of actin assembly. This diverse range of formin-activities is not fully explained through profilin-PLP interactions, as all ALS-associated variants bind a formin-derived PLP peptide with similar affinities. However, chemical denaturation experiments suggest that the folding stability of these profilins impact some of these effects on actin assembly. Thus, changes in profilin protein stability and alterations in actin filament polymerization may both contribute to the profilin-mediated actin disruptions in ALS.

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“…After 4 days in culture, the hippocampal neurons were transfected with a plasmid encoding for EB3-GFP (Stepanova et al ., 2003) using lipofectamine 2000. Twelve hours after transfection, time-lapse recordings were performed as described elsewhere (Pinto-Costa et al, 2020) using a Spinning Disk Confocal System Andor Revolution XD with an iXonEM+DU-897 camera and a IQ 1.10.1 software (Andor Tecnhology). To quantify comet growth speed, the Fiji KymoRescliceWide plugin was used to extract the kymographs, and the start/end positions of the traces defined with the Fiji Cell Counter plugin.…”

Section: Methodsmentioning

confidence: 99%

CLASP1 is essential for neonatal lung function and survival in mice

Pereira

Silva

Ferreira

et al. 2022

Preprint

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SummaryLife-threatening breathing problems due to incomplete lung development or acute respiratory distress are common in premature babies and respiratory diseases. Here we show that the microtubule plus-end-tracking protein CLASP1 is required for neonatal lung function and survival. CLASP1 is expressed in the lungs and associated respiratory structures throughout embryonic development. Clasp1 disruption in mice caused intrauterine growth restriction and neonatal lethality due to acute respiratory failure. Knockout animals showed impaired lung inflation associated with smaller rib cage formation, delayed fetal lung maturation and diaphragms with abnormal innervation. Live-cell analysis of microtubule dynamics in cultured hippocampal neurons revealed an increased catastrophe rate, consistent with a role of CLASP1 in neurite outgrowth. Gene expression studies further indicated that CLASP1 is required for normal lung cell differentiation. These findings unveil an unexpected link between the regulation of microtubule dynamics, respiratory muscle innervation and lung cell differentiation, essential for neonatal lung function and survival.

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Profilin 1 delivery tunes cytoskeletal dynamics toward CNS axon regeneration

Cited by 40 publications

References 67 publications

Profilin Isoforms in Health and Disease – All the Same but Different

Profilin Isoforms in Health and Disease – All the Same but Different

Biochemical characterization of actin assembly mechanisms with ALS-associated profilin variants

CLASP1 is essential for neonatal lung function and survival in mice

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