Molecular Neurobiology Group, Institute of Physiological Chemistry, Philipps-University of Marburg, 35032, Marburg, Germany.
Center for Mind, Brain and Behavior (CMBB), University of Marburg and Justus-Liebig-University Giessen, 35032, Marburg, Germany.
Cell Mol Life Sci. 2024 Aug 18;81(1):353. doi: 10.1007/s00018-024-05393-y.
The morphology of dendritic spines, the postsynaptic compartment of most excitatory synapses, decisively modulates the function of neuronal circuits as also evident from human brain disorders associated with altered spine density or morphology. Actin filaments (F-actin) form the backbone of spines, and a number of actin-binding proteins (ABP) have been implicated in shaping the cytoskeleton in mature spines. Instead, only little is known about the mechanisms that control the reorganization from unbranched F-actin of immature spines to the complex, highly branched cytoskeleton of mature spines. Here, we demonstrate impaired spine maturation in hippocampal neurons upon genetic inactivation of cyclase-associated protein 1 (CAP1) and CAP2, but not of CAP1 or CAP2 alone. We found a similar spine maturation defect upon overactivation of inverted formin 2 (INF2), a nucleator of unbranched F-actin with hitherto unknown synaptic function. While INF2 overactivation failed in altering spine density or morphology in CAP-deficient neurons, INF2 inactivation largely rescued their spine defects. From our data we conclude that CAPs inhibit INF2 to induce spine maturation. Since we previously showed that CAPs promote cofilin1-mediated cytoskeletal remodeling in mature spines, we identified them as a molecular switch that control transition from filopodia-like to mature spines.
树突棘的形态，即大多数兴奋性突触的后突触隔室，显著调节神经元回路的功能，这一点也可以从与脊柱密度或形态改变相关的人类大脑紊乱中得到证明。肌动蛋白丝（F-actin）构成脊柱的骨干，许多肌动蛋白结合蛋白（ABP）已被牵连到成熟脊柱中的细胞骨架形成中。相反，对于控制从未分支的 F-actin 到成熟脊柱的复杂、高度分支的细胞骨架的重组的机制，我们知之甚少。在这里，我们证明在环化酶相关蛋白 1（CAP1）和 CAP2 的基因失活后，海马神经元中的脊柱成熟受损，但 CAP1 或 CAP2 单独失活则不会。我们发现，在未分支 F-actin 的成核因子 2（INF2）的过度激活下，也会出现类似的脊柱成熟缺陷，INF2 是一种未分支 F-actin 的成核因子，具有迄今为止未知的突触功能。虽然在 CAP 缺失神经元中，INF2 的过度激活未能改变脊柱密度或形态，但 INF2 的失活在很大程度上挽救了它们的脊柱缺陷。根据我们的数据，我们得出结论，CAPs 抑制 INF2 以诱导脊柱成熟。由于我们之前表明 CAPs 促进成熟脊柱中的肌动蛋白丝结合蛋白 1（cofilin1）介导的细胞骨架重塑，因此我们将其鉴定为控制从丝状伪足样到成熟脊柱的过渡的分子开关。
