Mutual functional dependence of cyclase-associated protein 1 (CAP1) and cofilin1 in neuronal actin dynamics and growth cone function

Schneider, Friedhelm; Duong, Thuy-An; Metz, Isabell; Winkelmeier, Jannik; Hübner, Christian A.; Endesfelder, Ulrike; Rust, Marco B.

doi:10.1016/j.pneurobio.2021.102050

Cited by 22 publications

(51 citation statements)

References 68 publications

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“…CAP2 −/− mice were generated by breeding heterozygous CAP2 mice (CAP2 +/− ) obtained from the European Conditional Mouse Mutagenesis Program (EUCOMM). Generation of conditional CAP1 mice has been reported before [ 9 ]. CAP1-deficient hippocampal neurons were obtained from conditional CAP1 mice (CAP1 flx/flx ) additionally expressing a Cre transgene under control of the nestin promoter [ 23 ].…”

Section: Methodsmentioning

confidence: 99%

“…Thereafter, neurons were pelleted at 7000 rpm for 7 min, plated on 0.1 mg/mL poly- l -lysine-coated coverslips, and fixed 24 h later. The following constructs were used: GFP-CAP1, mCherry-CAP1, and myc-CAP1 [ 9 ], GFP-CAP2 and myc-CAP2 [ 19 ], and GFP (GeneScript, Piscataway, NJ, USA). Three different shRNAs were used to knockdown CAP2: sh2 (5′-CCTTTGAGAATGAGGATAA-3′), sh3 (5′-AGAAGTGGAGAGTGGAATA-3′), and sh4 (5′-CAGATGACAAGAAGACATA-3′).…”

Section: Methodsmentioning

confidence: 99%

“…By exploiting recombinant proteins and mutant yeast strains, studies of the past few years implicated CAP in various steps of the actin treadmilling mechanism, thereby identifying it as a crucial regulator of actin dynamics [ 3 , 4 , 5 , 6 , 7 , 8 ]. Specifically, these studies revealed a cooperation with the actin-depolymerizing protein ADF/cofilin in the dissociation of actin subunits from filamentous actin (F-actin) and, hence, in F-actin disassembly [ 5 , 7 , 9 ]. Moreover, they revealed a role for CAP in nucleotide exchange on globular actin monomers (G-actin) relevant for G-actin recycling and F-actin assembly [ 4 ], and they reported an inhibitory function towards the F-actin assembly factor, inverted formin 2 (INF2) [ 6 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, CAP2 dysregulation has been implicated in synaptic defects of Alzheimer’s disease [ 19 ]. Instead, hippocampal neurons from brain-specific CAP1-KO mice displayed an altered morphology and function of growth cones [ 9 ], dynamic F-actin-rich structures at the tip of neurites that sense environmental guidance cues and navigate axons through the developing brain to their target regions [ 22 ]. Consequently, neuron connectivity was compromised in CAP1-KO brains [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

“…Instead, hippocampal neurons from brain-specific CAP1-KO mice displayed an altered morphology and function of growth cones [ 9 ], dynamic F-actin-rich structures at the tip of neurites that sense environmental guidance cues and navigate axons through the developing brain to their target regions [ 22 ]. Consequently, neuron connectivity was compromised in CAP1-KO brains [ 9 ]. These findings are in line with a model in which CAP1 controls actin-dependent mechanisms during neuron differentiation, while CAP2 is relevant for actin regulation in differentiated neurons.…”

Section: Introductionmentioning

confidence: 99%

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Functional Redundancy of Cyclase-Associated Proteins CAP1 and CAP2 in Differentiating Neurons

Schneider

Metz

Khudayberdiev

et al. 2021

Cells

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Cyclase-associated proteins (CAPs) are evolutionary-conserved actin-binding proteins with crucial functions in regulating actin dynamics, the spatiotemporally controlled assembly and disassembly of actin filaments (F-actin). Mammals possess two family members (CAP1 and CAP2) with different expression patterns. Unlike most other tissues, both CAPs are expressed in the brain and present in hippocampal neurons. We recently reported crucial roles for CAP1 in growth cone function, neuron differentiation, and neuron connectivity in the mouse brain. Instead, CAP2 controls dendritic spine morphology and synaptic plasticity, and its dysregulation contributes to Alzheimer’s disease pathology. These findings are in line with a model in which CAP1 controls important aspects during neuron differentiation, while CAP2 is relevant in differentiated neurons. We here report CAP2 expression during neuron differentiation and its enrichment in growth cones. We therefore hypothesized that CAP2 is relevant not only in excitatory synapses, but also in differentiating neurons. However, CAP2 inactivation neither impaired growth cone morphology and motility nor neuron differentiation. Moreover, CAP2 mutant mice did not display any obvious changes in brain anatomy. Hence, differently from CAP1, CAP2 was dispensable for neuron differentiation and brain development. Interestingly, overexpression of CAP2 rescued not only growth cone size in CAP1-deficient neurons, but also their morphology and differentiation. Our data provide evidence for functional redundancy of CAP1 and CAP2 in differentiating neurons, and they suggest compensatory mechanisms in single mutant neurons.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Functional Redundancy of Cyclase-Associated Proteins CAP1 and CAP2 in Differentiating Neurons

Schneider

Metz

Khudayberdiev

et al. 2021

Cells

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A homozygous CAP2 pathogenic variant in a neonate presenting with rapidly progressive cardiomyopathy and nemaline rods

Sharavana

Sebastian

Baker

et al. 2021

American J of Med Genetics Pt A

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Nemaline Myopathy (NM) is a disorder of skeletal muscles caused by mutations in sarcomere proteins and characterized by accumulation of microscopic rod or threadlike structures (nemaline bodies) in skeletal muscles. Patients diagnosed with both NM and infantile cardiomyopathy are very rare. A male infant presented, within the first few hours of life, with severe dilated cardiomyopathy, biventricular dysfunction and left ventricular noncompaction. A muscle biopsy on the 8th day of life from the

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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.

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Mutual functional dependence of cyclase-associated protein 1 (CAP1) and cofilin1 in neuronal actin dynamics and growth cone function

Cited by 22 publications

References 68 publications

Functional Redundancy of Cyclase-Associated Proteins CAP1 and CAP2 in Differentiating Neurons

Functional Redundancy of Cyclase-Associated Proteins CAP1 and CAP2 in Differentiating Neurons

A homozygous CAP2 pathogenic variant in a neonate presenting with rapidly progressive cardiomyopathy and nemaline rods

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

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