Eps8 regulates axonal filopodia in hippocampal neurons in response to brain-derived neurotrophic factor (BDNF).

The regulation of filopodia plays a crucial role during neuronal development and synaptogenesis. Axonal filopodia, which are known to originate presynaptic specializations, are regulated in response to neurotrophic factors. The structural components of filopodia are actin filaments, whose dynamics a...

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Autores principales:	Elisabetta Menna, Andrea Disanza, Cinzia Cagnoli, Ursula Schenk, Giuliana Gelsomino, Emanuela Frittoli, Maud Hertzog, Nina Offenhauser, Corinna Sawallisch, Hans-Jürgen Kreienkamp, Frank B Gertler, Pier Paolo Di Fiore, Giorgio Scita, Michela Matteoli
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2009
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/3c7dc63bc6aa4679a9c376ccaa2be0f5
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spelling	oai:doaj.org-article:3c7dc63bc6aa4679a9c376ccaa2be0f52021-11-25T05:34:07ZEps8 regulates axonal filopodia in hippocampal neurons in response to brain-derived neurotrophic factor (BDNF).1544-91731545-788510.1371/journal.pbio.1000138https://doaj.org/article/3c7dc63bc6aa4679a9c376ccaa2be0f52009-06-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19564905/pdf/?tool=EBIhttps://doaj.org/toc/1544-9173https://doaj.org/toc/1545-7885The regulation of filopodia plays a crucial role during neuronal development and synaptogenesis. Axonal filopodia, which are known to originate presynaptic specializations, are regulated in response to neurotrophic factors. The structural components of filopodia are actin filaments, whose dynamics and organization are controlled by ensembles of actin-binding proteins. How neurotrophic factors regulate these latter proteins remains, however, poorly defined. Here, using a combination of mouse genetic, biochemical, and cell biological assays, we show that genetic removal of Eps8, an actin-binding and regulatory protein enriched in the growth cones and developing processes of neurons, significantly augments the number and density of vasodilator-stimulated phosphoprotein (VASP)-dependent axonal filopodia. The reintroduction of Eps8 wild type (WT), but not an Eps8 capping-defective mutant, into primary hippocampal neurons restored axonal filopodia to WT levels. We further show that the actin barbed-end capping activity of Eps8 is inhibited by brain-derived neurotrophic factor (BDNF) treatment through MAPK-dependent phosphorylation of Eps8 residues S624 and T628. Additionally, an Eps8 mutant, impaired in the MAPK target sites (S624A/T628A), displays increased association to actin-rich structures, is resistant to BDNF-mediated release from microfilaments, and inhibits BDNF-induced filopodia. The opposite is observed for a phosphomimetic Eps8 (S624E/T628E) mutant. Thus, collectively, our data identify Eps8 as a critical capping protein in the regulation of axonal filopodia and delineate a molecular pathway by which BDNF, through MAPK-dependent phosphorylation of Eps8, stimulates axonal filopodia formation, a process with crucial impacts on neuronal development and synapse formation.Elisabetta MennaAndrea DisanzaCinzia CagnoliUrsula SchenkGiuliana GelsominoEmanuela FrittoliMaud HertzogNina OffenhauserCorinna SawallischHans-Jürgen KreienkampFrank B GertlerPier Paolo Di FioreGiorgio ScitaMichela MatteoliPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Biology, Vol 7, Iss 6, p e1000138 (2009)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Elisabetta Menna Andrea Disanza Cinzia Cagnoli Ursula Schenk Giuliana Gelsomino Emanuela Frittoli Maud Hertzog Nina Offenhauser Corinna Sawallisch Hans-Jürgen Kreienkamp Frank B Gertler Pier Paolo Di Fiore Giorgio Scita Michela Matteoli Eps8 regulates axonal filopodia in hippocampal neurons in response to brain-derived neurotrophic factor (BDNF).
description	The regulation of filopodia plays a crucial role during neuronal development and synaptogenesis. Axonal filopodia, which are known to originate presynaptic specializations, are regulated in response to neurotrophic factors. The structural components of filopodia are actin filaments, whose dynamics and organization are controlled by ensembles of actin-binding proteins. How neurotrophic factors regulate these latter proteins remains, however, poorly defined. Here, using a combination of mouse genetic, biochemical, and cell biological assays, we show that genetic removal of Eps8, an actin-binding and regulatory protein enriched in the growth cones and developing processes of neurons, significantly augments the number and density of vasodilator-stimulated phosphoprotein (VASP)-dependent axonal filopodia. The reintroduction of Eps8 wild type (WT), but not an Eps8 capping-defective mutant, into primary hippocampal neurons restored axonal filopodia to WT levels. We further show that the actin barbed-end capping activity of Eps8 is inhibited by brain-derived neurotrophic factor (BDNF) treatment through MAPK-dependent phosphorylation of Eps8 residues S624 and T628. Additionally, an Eps8 mutant, impaired in the MAPK target sites (S624A/T628A), displays increased association to actin-rich structures, is resistant to BDNF-mediated release from microfilaments, and inhibits BDNF-induced filopodia. The opposite is observed for a phosphomimetic Eps8 (S624E/T628E) mutant. Thus, collectively, our data identify Eps8 as a critical capping protein in the regulation of axonal filopodia and delineate a molecular pathway by which BDNF, through MAPK-dependent phosphorylation of Eps8, stimulates axonal filopodia formation, a process with crucial impacts on neuronal development and synapse formation.
format	article
author	Elisabetta Menna Andrea Disanza Cinzia Cagnoli Ursula Schenk Giuliana Gelsomino Emanuela Frittoli Maud Hertzog Nina Offenhauser Corinna Sawallisch Hans-Jürgen Kreienkamp Frank B Gertler Pier Paolo Di Fiore Giorgio Scita Michela Matteoli
author_facet	Elisabetta Menna Andrea Disanza Cinzia Cagnoli Ursula Schenk Giuliana Gelsomino Emanuela Frittoli Maud Hertzog Nina Offenhauser Corinna Sawallisch Hans-Jürgen Kreienkamp Frank B Gertler Pier Paolo Di Fiore Giorgio Scita Michela Matteoli
author_sort	Elisabetta Menna
title	Eps8 regulates axonal filopodia in hippocampal neurons in response to brain-derived neurotrophic factor (BDNF).
title_short	Eps8 regulates axonal filopodia in hippocampal neurons in response to brain-derived neurotrophic factor (BDNF).
title_full	Eps8 regulates axonal filopodia in hippocampal neurons in response to brain-derived neurotrophic factor (BDNF).
title_fullStr	Eps8 regulates axonal filopodia in hippocampal neurons in response to brain-derived neurotrophic factor (BDNF).
title_full_unstemmed	Eps8 regulates axonal filopodia in hippocampal neurons in response to brain-derived neurotrophic factor (BDNF).
title_sort	eps8 regulates axonal filopodia in hippocampal neurons in response to brain-derived neurotrophic factor (bdnf).
publisher	Public Library of Science (PLoS)
publishDate	2009
url	https://doaj.org/article/3c7dc63bc6aa4679a9c376ccaa2be0f5
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Eps8 regulates axonal filopodia in hippocampal neurons in response to brain-derived neurotrophic factor (BDNF).

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