| Title: |
The actin-binding protein CAP1 represses MRTF-SRF–dependent gene expression in mouse cerebral cortex. |
| Authors: |
Khudayberdiev, Sharof; Weiss, Kerstin; Heinze, Anika; Colombaretti, Dalila; Trausch, Nathan; Linne, Uwe; Rust, Marco B. |
| Source: |
Science Signaling; 5/7/2024, Vol. 17 Issue 835, p1-16, 16p |
| Subject Terms: |
Microfilament proteins; Cerebral cortex; Serum response factor; Gene expression; Neural circuitry; Transcription factors |
| Abstract: |
Serum response factor (SRF) is an essential transcription factor for brain development and function. Here, we explored how an SRF cofactor, the actin monomer-sensing myocardin-related transcription factor MRTF, is regulated in mouse cortical neurons. We found that MRTF-dependent SRF activity in vitro and in vivo was repressed by cyclase-associated protein CAP1. Inactivation of the actin-binding protein CAP1 reduced the amount of actin monomers in the cytoplasm, which promoted nuclear MRTF translocation and MRTF-SRF activation. This function was independent of cofilin1 and actin-depolymerizing factor, and CAP1 loss of function in cortical neurons was not compensated by endogenous CAP2. Transcriptomic and proteomic analyses of cerebral cortex lysates from wild-type and Cap1 knockout mice supported the role of CAP1 in repressing MRTF-SRF–dependent signaling in vivo. Bioinformatic analysis identified likely MRTF-SRF target genes, which aligned with the transcriptomic and proteomic results. Together with our previous studies that implicated CAP1 in axonal growth cone function as well as the morphology and plasticity of excitatory synapses, our findings establish CAP1 as a crucial actin regulator in the brain relevant for formation of neuronal networks. Editor's summary: The transcription factor SRF and its cofactor MRTF induce cytoskeletal dynamics that mediate changes in neuronal morphology and, thus, the formation and maintenance of neural circuitry in the brain. Khudayberdiev et al. found that MRTF-SRF signaling in mouse cortical neurons was regulated by the cyclase-associated protein CAP1. Analysis of the cerebral cortices of Cap1 knockout mice and isolated cortical neurons showed that CAP1 bound to the actin cytoskeleton and increased the amount of actin monomers in the cytoplasm. These actin monomers bound to and sequestered MRTF in the cytoplasm, thereby reducing MRTF-dependent SRF transcriptional activity. The findings, which include a multiomic resource for further exploration, provide insight into the regulation of cytoskeleton-associated signaling in neuronal development and function. —Leslie K. Ferrarelli [ABSTRACT FROM AUTHOR] |
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| Database: |
Complementary Index |