Transient reduction in dendritic spine density in brain-specific profilin1 mutant mice is associated with behavioral deficits

Sungur, A. Özge; Zeitouny, Caroline; Gabele, Lea; Metz, Isabell; Wöhr, Markus; Michaelsen-Preusse, Kristin; Rust, Marco B.

doi:10.3389/fnmol.2022.952782

Cited by 5 publications

(2 citation statements)

References 55 publications

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“…Notably, CAP1 comprises several conserved domains allowing interaction with molecules others than actin and cofilin1. To date, a number of interaction partners have been found for CAP1 or its homologs (for review: [26,46,58,59], including established regulators of spine morphology, such as the ABP profilin [1,32,39,40,70], the proteinase MMP-9 [71,73], the tyrosine kinases Abl1 and Abl2 [33,36,44], focal adhesion kinase [42,67], and glycogen synthase kinase 3 (GSK3; [43,48]. Normalization of spine parameters in CAP1-KO neurons upon expression of a CAP1 variant with a mutated prolinerich motif (CAP1-P1) suggested that its proline-rich domain and, hence, its interaction with profilin were not relevant in spines.…”

Section: Discussionmentioning

confidence: 99%

Functional interdependence of the actin regulators CAP1 and cofilin1 in control of dendritic spine morphology

Heinze

Schuldt

Khudayberdiev

et al. 2022

Preprint

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The vast majority of excitatory synapses are formed on small dendritic protrusions termed dendritic spines. Dendritic spines vary in size and density that are crucial determinants of excitatory synaptic transmission. Aberrations in spine morphogenesis can compromise brain function and have been associated with neuropsychiatric disorders. Actin filaments (F-actin) are the major structural component of dendritic spines and therefore actin-binding proteins (ABP) that control F-actin dis-/assembly moved into the focus as critical regulators of brain function. Studies of the past decade identified the ABP cofilin1 as a key regulator of spine morphology, synaptic transmission and behavior, and they emphasized the necessity for a tight control of cofilin1 to ensure proper brain function. Here, we report spine enrichment of cyclase-associated protein 1 (CAP1), a conserved multidomain protein with largely unknown physiological functions. Super-resolution microscopy and live cell imaging of CAP1-deficient hippocampal neurons revealed impaired synaptic F-actin organization and dynamics associated with alterations in spine morphology. Mechanistically, we found that CAP1 cooperates with cofilin1 in spines and that its helical folded domain is relevant for this interaction. Moreover, our data proved functional interdependence of CAP1 and cofilin1 in control of spine morphology. In summary, we identified CAP1 as a novel regulator of the postsynaptic actin cytoskeleton that is essential for synaptic cofilin1 activity.

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Section: Discussionmentioning

confidence: 99%

Functional interdependence of the actin regulators CAP1 and cofilin1 in control of dendritic spine morphology

Heinze

Schuldt

Khudayberdiev

et al. 2022

Preprint

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show abstract

“…In addition, an activity-dependent translocation into dendritic spines could be shown for both, PFN1 and PFN2a ( Ackermann and Matus, 2003 ). Non-etheless, both isoforms were shown to be differentially engaged in the regulation of synaptic actin as PFN1 was found to be important for dendritic spine formation ( Sungur et al, 2022 ) while PFN2a was shown to be involved in spine stabilization, synaptic function as well as activity-dependent structural plasticity ( Michaelsen et al, 2010a ; Michaelsen-Preusse et al, 2016 ). In line with this, although both isoforms share certain functional redundancies, the loss of one isoform cannot be fully compensated by the other ( Michaelsen-Preusse et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Phosphorylation of the actin-binding protein profilin2a at S137 modulates bidirectional structural plasticity at dendritic spines

Cornelius

Haak²,

Rothkegel³

et al. 2023

Front. Cell Dev. Biol.

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Background: Synaptic plasticity requires constant adaptation of functional and structural features at individual synaptic connections. Rapid re-modulation of the synaptic actin cytoskeleton provides the scaffold orchestrating both morphological and functional modifications. A major regulator of actin polymerization not only in neurons but also in various other cell types is the actin-binding protein profilin. While profilin is known to mediate the ADP to ATP exchange at actin monomers through its direct interaction with G-actin, it additionally is able to influence actin dynamics by binding to membrane-bound phospholipids as phosphatidylinositol (4,5)-bisphosphate (PIP2) as well as several other proteins containing poly-L-proline motifs including actin modulators like Ena/VASP, WAVE/WASP or formins. Notably, these interactions are proposed to be mediated by a fine-tuned regulation of post-translational phosphorylation of profilin. However, while phosphorylation sites of the ubiquitously expressed isoform profilin1 have been described and analyzed previously, there is still only little known about the phosphorylation of the profilin2a isoform predominantly expressed in neurons.Methods: Here, utilizing a knock-down/knock-in approach, we replaced endogenously expressed profilin2a by (de)phospho-mutants of S137 known to alter actin-, PIP2 and PLP-binding properties of profilin2a and analyzed their effect on general actin dynamics as well as activity-dependent structural plasticity.Results and Discussion: Our findings suggest that a precisely timed regulation of profilin2a phosphorylation at S137 is needed to mediate actin dynamics and structural plasticity bidirectionally during long-term potentiation and long-term depression, respectively.

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Functional interdependence of the actin regulators CAP1 and cofilin1 in control of dendritic spine morphology

Heinze

Schuldt

Khudayberdiev

et al. 2022

Cell. Mol. Life Sci.

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The vast majority of excitatory synapses are formed on small dendritic protrusions termed dendritic spines. Dendritic spines vary in size and density that are crucial determinants of excitatory synaptic transmission. Aberrations in spine morphogenesis can compromise brain function and have been associated with neuropsychiatric disorders. Actin filaments (F-actin) are the major structural component of dendritic spines, and therefore, actin-binding proteins (ABP) that control F-actin dis-/assembly moved into the focus as critical regulators of brain function. Studies of the past decade identified the ABP cofilin1 as a key regulator of spine morphology, synaptic transmission, and behavior, and they emphasized the necessity for a tight control of cofilin1 to ensure proper brain function. Here, we report spine enrichment of cyclase-associated protein 1 (CAP1), a conserved multidomain protein with largely unknown physiological functions. Super-resolution microscopy and live cell imaging of CAP1-deficient hippocampal neurons revealed impaired synaptic F-actin organization and dynamics associated with alterations in spine morphology. Mechanistically, we found that CAP1 cooperates with cofilin1 in spines and that its helical folded domain is relevant for this interaction. Moreover, our data proved functional interdependence of CAP1 and cofilin1 in control of spine morphology. In summary, we identified CAP1 as a novel regulator of the postsynaptic actin cytoskeleton that is essential for synaptic cofilin1 activity.

show abstract

Transient reduction in dendritic spine density in brain-specific profilin1 mutant mice is associated with behavioral deficits

Cited by 5 publications

References 55 publications

Functional interdependence of the actin regulators CAP1 and cofilin1 in control of dendritic spine morphology

Functional interdependence of the actin regulators CAP1 and cofilin1 in control of dendritic spine morphology

Phosphorylation of the actin-binding protein profilin2a at S137 modulates bidirectional structural plasticity at dendritic spines

Functional interdependence of the actin regulators CAP1 and cofilin1 in control of dendritic spine morphology

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