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Schlagwörter:
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Zusammenfassung:
Neuron connectivity depends on growth cones that navigate axons through
the developing brain. Growth cones protrude and retract actin-rich
structures to sense guidance cues. These cues control local actin
dynamics and steer growth cones towards attractants and away from
repellents, thereby directing axon outgrowth. Hence, actin binding
proteins (ABPs) moved into the focus as critical regulators of neuron
connectivity. We found cyclase-associated protein 1 (CAP1), an ABP with
unknown brain function, abundant in growth cones. Super-resolution
microscopy and live cell imaging combined with pharmacological
approaches on hippocampal neurons from gene-targeted mice revealed a
crucial role for CAP1 in actin dynamics that is critical for growth cone
morphology and function. Growth cone defects in CAP1 knockout (KO)
neurons compromised neuron differentiation and was associated with
impaired neuron connectivity in CAP1-KO brains. Mechanistically, by
rescue experiments in double KO neurons lacking CAP1 and the key actin
regulator cofilin1, we demonstrated that CAP1 was essential for cofilin1
function in growth cone actin dynamics and morphology and vice versa.
Together, we identified CAP1 as a novel actin regulator in growth cones
that was relevant for neuron connectivity, and we demonstrated
functional interdependence of CAP1 and cofilin1 in neuronal actin
dynamics and growth cone function.
