Dynamic recruitment of the curvature-sensitive protein ArhGAP44 to nanoscale membrane deformations limits exploratory filopodia initiation in neurons
| Autor: | Sean R. Collins, Tobias Meyer, Feng-Chiao Tsai, Maja Matis, Milos Galic, Samuel Bandara |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
rac1 GTP-Binding Protein
Wistar Cell membrane Synapse Models cell biology rat Pseudopodia Biology (General) Neurons General Neuroscience GTPase-Activating Proteins Brain General Medicine Reference Standards Dendritic filopodia Transport protein Cell biology Protein Transport Actin Cytoskeleton medicine.anatomical_structure Spinal Cord Gene Knockdown Techniques Medicine Female actin Filopodia Research Article QH301-705.5 1.1 Normal biological development and functioning Science macromolecular substances Biology Myosins Models Biological General Biochemistry Genetics and Molecular Biology Fetus Underpinning research medicine Animals Humans Rats Wistar General Immunology and Microbiology Cell Membrane Neurosciences Cell Biology Dendrites Biological Actin cytoskeleton neuron Rats nervous system membrane curvature Nanoparticles Biochemistry and Cell Biology Neuron |
| Zdroj: | Galic, M; Tsai, F-C; Collins, SR; Matis, M; Bandara, S; & Meyer, T. (2014). Dynamic recruitment of the curvature-sensitive protein ArhGAP44 to nanoscale membrane deformations limits exploratory filopodia initiation in neurons. ELIFE, 3, e03116. doi: 10.7554/eLife.03116. UC Davis: Retrieved from: http://www.escholarship.org/uc/item/94d5c6jc eLife, Vol 3 (2014) eLife |
| DOI: | 10.7554/eLife.03116. |
| Popis: | In the vertebrate central nervous system, exploratory filopodia transiently form on dendritic branches to sample the neuronal environment and initiate new trans-neuronal contacts. While much is known about the molecules that control filopodia extension and subsequent maturation into functional synapses, the mechanisms that regulate initiation of these dynamic, actin-rich structures have remained elusive. Here, we find that filopodia initiation is suppressed by recruitment of ArhGAP44 to actin-patches that seed filopodia. Recruitment is mediated by binding of a membrane curvature-sensing ArhGAP44 N-BAR domain to plasma membrane sections that were deformed inward by acto-myosin mediated contractile forces. A GAP domain in ArhGAP44 triggers local Rac-GTP hydrolysis, thus reducing actin polymerization required for filopodia formation. Additionally, ArhGAP44 expression increases during neuronal development, concurrent with a decrease in the rate of filopodia formation. Together, our data reveals a local auto-regulatory mechanism that limits initiation of filopodia via protein recruitment to nanoscale membrane deformations. DOI: http://dx.doi.org/10.7554/eLife.03116.001 eLife digest Our brains contain a vast network of many billions of cells that communicate with, and are connected to, each other. Each brain cell, or neuron, can form connections with as many as 10,000 other neurons—and signals pass from one neuron to the next at sites known as synapses. A neuron's surface has numerous finger-like protrusions known as filopodia that are important for sensing the environment around the cells. Filopodia are highly changeable and constantly extend and retract as the filaments that support them—which are made up of a protein called actin—grow and shrink back. Neurons use their filopodia to explore and seek out other neurons in the brain, and when they make contact with the right neuron, it leads to the formation of a synapse. However, how filopodial extensions begin to grow—and what stops a neuron from forming too many filopodia—is not fully understood. Galic et al. now show that a protein called ArhGAP44 limits the formation of new filopodia in neurons. The ArhGAP44 protein is recruited to patches of the surface membrane that have a lot of actin and that curve inwards. ArhGAP44 then locally inhibits other proteins that are normally required to extend the actin filaments and drive the growth of filopodia out from the surface of the cell. Galic et al. also show that more ArhGAP44 is produced with age—levels are low in embryos and high in adults—and this increase in the amount of protein correlates with a decrease in the number of filopodia formed. When Galic et al. engineered rat neurons to produce more of the ArhGAP44 protein, fewer filopodia formed on the surface of the neurons. Decreasing the amount of this protein had the opposite effect. Moreover, ArhGAP44 was shown to mainly stop new filopodia from forming and had little effect on existing filopodia. Together, these findings suggest that ArhGAP44 may help neurons transition from a dynamic exploratory mode to a mature, more static, state; this is a characteristic of the development of the nervous system. DOI: http://dx.doi.org/10.7554/eLife.03116.002 |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|