EVL and MIM/MTSS1 regulate actin cytoskeletal remodeling to promote dendritic filopodia in neurons

Parker, Sara S.; Ly, Kenneth Tran; Grant, Adam; Sweetland, Jillian; Wang, Ashley M; Parker, James D; Roman, Mackenzie R.; Saboda, Kathylynn; Roe, Denise J.; Padi, Megha; Wolgemuth, Charles W.; Langlais, Paul; Mouneimne, Ghassan

doi:10.1083/jcb.202106081

Cited by 12 publications

(5 citation statements)

References 113 publications

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“…For example, dendritic protrusions are more stable and long-lived than growth cone filopodia ( Menon et al. , 2015 ; Parker et al. , 2023 ).…”

Section: Discussionmentioning

confidence: 99%

The E3 ubiquitin ligase TRIM9 regulates synaptic function and actin dynamics in response to netrin-1

McCormick,

Evans,

Barker

et al. 2024

MBoC

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During neuronal development, dynamic filopodia emerge from dendrites and mature into functional dendritic spines during synaptogenesis. Dendritic filopodia and spines respond to extracellular cues, influencing dendritic spine shape and size as well as synaptic function. Previously, the E3 ubiquitin ligase TRIM9 was shown to regulate filopodia in early stages of neuronal development, including netrin-1 dependent axon guidance and branching. Here we demonstrate TRIM9 also localizes to dendritic filopodia and spines of murine cortical and hippocampal neurons during synaptogenesis and is required for synaptic responses to netrin. In particular, TRIM9 is enriched in the post-synaptic density (PSD) within dendritic spines and loss of Trim9 alters the PSD proteome, including the actin cytoskeleton landscape. While netrin exposure induces accumulation of the Arp2/3 complex and filamentous actin in dendritic spine heads, this response is disrupted by genetic deletion of Trim9. In addition, we document changes in the synaptic receptors associated with loss of Trim9. These defects converge on a loss of netrin-dependent increases in neuronal firing rates, indicating TRIM9 is required downstream of synaptic netrin-1 signaling. We propose TRIM9 regulates cytoskeletal dynamics in dendritic spines and is required for the proper response to synaptic stimuli.

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“…For example, dendritic protrusions are more stable and long-lived than growth cone filopodia ( Menon et al. , 2015 ; Parker et al. , 2023 ).…”

Section: Discussionmentioning

confidence: 99%

The E3 ubiquitin ligase TRIM9 regulates synaptic function and actin dynamics in response to netrin-1

McCormick,

Evans,

Barker

et al. 2024

MBoC

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show abstract

“…MIM is also able to interact with positive membrane curvature, utilizing amphipathic α helices within the I-BAR domain that are inserted into the membrane ( Drin et al, 2007 ; Bhatia et al, 2009 ). In addition, MIM harbors a proline-rich domain and a C-terminal WH2 domain that facilitates interaction with Cortactin (through its SH3 domain) and with the actin cytoskeleton, providing an extensive framework for dynamic membrane remodeling ( Quinones et al, 2010 ; Lin et al, 2005 ; Mattila et al, 2003 ; Parker et al, 2023 ).…”

Section: Discussionmentioning

confidence: 99%

Fusion pore dynamics of large secretory vesicles define a distinct mechanism of exocytosis

Biton,

Scher,

Carmon

et al. 2023

Journal of Cell Biology

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Exocrine cells utilize large secretory vesicles (LSVs) up to 10 μm in diameter. LSVs fuse with the apical surface, often recruiting actomyosin to extrude their content through dynamic fusion pores. The molecular mechanism regulating pore dynamics remains largely uncharacterized. We observe that the fusion pores of LSVs in the Drosophila larval salivary glands expand, stabilize, and constrict. Arp2/3 is essential for pore expansion and stabilization, while myosin II is essential for pore constriction. We identify several Bin-Amphiphysin-Rvs (BAR) homology domain proteins that regulate fusion pore expansion and stabilization. We show that the I-BAR protein Missing-in-Metastasis (MIM) localizes to the fusion site and is essential for pore expansion and stabilization. The MIM I-BAR domain is essential but not sufficient for localization and function. We conclude that MIM acts in concert with actin, myosin II, and additional BAR-domain proteins to control fusion pore dynamics, mediating a distinct mode of exocytosis, which facilitates actomyosin-dependent content release that maintains apical membrane homeostasis during secretion.

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“…Impairment of Ena/VASP activity after neurite initiation disrupts growth cone filopodia formation and responses to guidance cues ( Lebrand et al, 2004 ). Finally, VASP and EVL play a role in dendritic filopodia and dendritic spine formation ( Lin et al, 2010 ; Parker et al, 2023 ).…”

Section: Introductionmentioning

confidence: 99%

Multi-monoubiquitylation controls VASP-mediated actin dynamics

McCormick,

Suarez,

Herring

et al. 2024

Journal of Cell Science

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The actin cytoskeleton performs multiple cellular functions, and as such, actin polymerization must be tightly regulated. We previously demonstrated that reversible, non-degradative ubiquitination regulates the function of the actin polymerase VASP in developing neurons. However, the underlying mechanism of how ubiquitination impacts VASP activity was unknown. Here we show that mimicking multi-monoubiquitination of VASP at K240 and K286 negatively regulates VASP interactions with actin. Using in vitro biochemical assays, we demonstrate the reduced ability of multi-monoubiquitinated VASP to bind, bundle, and elongate actin filaments. However, multi-monoubiquitinated VASP maintained the ability to bind and protect barbed ends from capping protein. Lastly, we demonstrate the electroporation of recombinant multi-monoubiquitinated VASP protein altered cell spreading morphology. Collectively, these results suggest a mechanism in which ubiquitination controls VASP-mediated actin dynamics.

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EVL and MIM/MTSS1 regulate actin cytoskeletal remodeling to promote dendritic filopodia in neurons

Cited by 12 publications

References 113 publications

The E3 ubiquitin ligase TRIM9 regulates synaptic function and actin dynamics in response to netrin-1

The E3 ubiquitin ligase TRIM9 regulates synaptic function and actin dynamics in response to netrin-1

Fusion pore dynamics of large secretory vesicles define a distinct mechanism of exocytosis

Multi-monoubiquitylation controls VASP-mediated actin dynamics

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