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Published on: July 5, 2019
Brain-specific Drp1 regulates postsynaptic endocytosis and dendrite formation independently of mitochondrial division
Kie Itoh1, Daisuke Murata1, Takashi Kato1
1Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, United States.
Abstract:
Dynamin-related protein 1 (Drp1) divides mitochondria as a mechano-chemical GTPase. However, the function of Drp1 beyond mitochondrial division is largely unknown. Multiple Drp1 isoforms are produced through mRNA splicing. One such isoform, Drp1ABCD, contains all four alternative exons and is specifically expressed in the brain. Here, we studied the function of Drp1ABCD in mouse neurons in both culture and animal systems using isoform-specific knockdown by shRNA and isoform-specific knockout by CRISPR/Cas9. We found that the expression of Drp1ABCD is induced during postnatal brain development. Drp1ABCD is enriched in dendritic spines and regulates postsynaptic clathrin-mediated endocytosis by positioning the endocytic zone at the postsynaptic density, independently of mitochondrial division. Drp1ABCD loss promotes the formation of ectopic dendrites in neurons and enhanced sensorimotor gating behavior in mice. These data reveal that Drp1ABCD controls postsynaptic endocytosis, neuronal morphology and brain function.
Insights
Dynamin-related protein 1 isoform ABCD (Drp1ABCD) in neurons regulates postsynaptic endocytosis and neuronal structure. Loss of Drp1ABCD impacts brain development and sensorimotor gating behavior in mice.
Area of Science:
- Neuroscience
- Cell Biology
- Molecular Biology
Background:
- Dynamin-related protein 1 (Drp1) is known for mitochondrial division.
- Its functions beyond mitochondrial dynamics are not well understood.
- Alternative splicing generates multiple Drp1 isoforms, including brain-specific Drp1ABCD.
Purpose of the Study:
- To investigate the function of the Drp1ABCD isoform in mouse neurons.
- To determine the role of Drp1ABCD in postsynaptic processes and neuronal morphology.
- To explore the impact of Drp1ABCD on brain function and behavior.
Main Methods:
- Isoform-specific knockdown using shRNA in cultured neurons.
- Isoform-specific knockout using CRISPR/Cas9 in mouse models.
- Analysis of dendritic spine morphology and postsynaptic endocytosis.
- Assessment of sensorimotor gating behavior in mice.
Main Results:
- Drp1ABCD expression is upregulated during postnatal brain development.
- Drp1ABCD localizes to dendritic spines and regulates clathrin-mediated endocytosis independently of mitochondrial division.
- Loss of Drp1ABCD leads to ectopic dendrite formation and altered sensorimotor gating.
Conclusions:
- Drp1ABCD plays a critical role in postsynaptic endocytosis.
- Drp1ABCD influences neuronal morphology and brain function.
- This isoform is a key regulator of neuronal development and behavior.
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