KLHL17/Actinfilin, a brain-specific gene associated with infantile spasms and autism, regulates dendritic spine enlargem
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RESEARCH
KLHL17/Actinfilin, a brain‑specific gene associated with infantile spasms and autism, regulates dendritic spine enlargement Hsiao‑Tang Hu, Tzyy‑Nan Huang and Yi‑Ping Hsueh*
Abstract Background: Dendritic spines, the actin-rich protrusions emerging from dendrites, are the subcellular locations of excitatory synapses in the mammalian brain. Many actin-regulating molecules modulate dendritic spine morphology. Since dendritic spines are neuron-specific structures, it is reasonable to speculate that neuron-specific or -predomi‑ nant factors are involved in dendritic spine formation. KLHL17 (Kelch-like 17, also known as Actinfilin), an actin-bind‑ ing protein, is predominantly expressed in brain. Human genetic study has indicated an association of KLHL17/Actin‑ filin with infantile spasms, a rare form of childhood epilepsy also resulting in autism and mental retardation, indicating that KLHL17/Actinfilin plays a role in neuronal function. However, it remains elusive if and how KLHL17/Actinfilin regulates neuronal development and brain function. Methods: Fluorescent immunostaining and electrophysiological recording were performed to evaluate dendritic spine formation and activity in cultured hippocampal neurons. Knockdown and knockout of KLHL17/Actinfilin and expression of truncated fragments of KLHL17/Actinfilin were conducted to investigate the function of KLHL17/Actinfi‑ lin in neurons. Mouse behavioral assays were used to evaluate the role of KLHL17/Actinfilin in brain function. Results: We found that KLHL17/Actinfilin tends to form circular puncta in dendritic spines and are surrounded by or adjacent to F-actin. Klhl17 deficiency impairs F-actin enrichment at dendritic spines. Knockdown and knockout of KLHL17/Actinfilin specifically impair dendritic spine enlargement, but not the density or length of dendritic spines. Both N-terminal Broad-Complex, Tramtrack and Bric-a-brac (BTB) domain and C-terminal Kelch domains of KLHL17/ Actinfilin are required for F-actin remodeling and enrichment at dendritic spines, as well as dendritic spine enlarge‑ ment. A reduction of postsynaptic and presynsptic markers at dendritic spines and altered mEPSC profiles due to Klhl17 deficiency evidence impaired synaptic activity in Klhl17-deficient neurons. Our behavioral assays further indicate that Klhl17 deficiency results in hyperactivity and reduced social interaction, strengthening evidence for the physiological role of KLHL17/Actinfilin. Conclusion: Our findings provide evidence that KLHL17/Actinfilin modulates F-actin remodeling and contributes to regulation of neuronal morphogenesis, maturation and activity, which is likely relevant to behavioral impairment in Klhl17-deficient mice. Trial registration Non-applicable. Keywords: Actinfilin, F-actin cytoskeleton, Infantile spasms, Kelch-like 17, Dendritic spine enlargement
*Correspondence: [email protected] Institute of Molecular Biology, Academia Sinica, 128, Academia Road, Section 2, Taipei 11529, Taiwan, Republic of China © The Author(s) 2020. Ope
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