Overexpression of Lin28A in neural progenitor cells in vivo does not lead to brain tumor formation but results in reduced spine density

Abstract LIN28A overexpression has been identified in malignant brain tumors called embryonal tumors with multilayered rosettes (ETMR) but its specific role during brain development remains largely unknown. Radial glia cells of the ventricular zone (VZ) are proposed as a cell of origin for ETMR. We...

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Autores principales:	Maximilian Middelkamp, Lisa Ruck, Christoph Krisp, Piotr Sumisławski, Behnam Mohammadi, Matthias Dottermusch, Valerie Meister, Lukas Küster, Hartmut Schlüter, Sabine Windhorst, Julia E. Neumann
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	LIN28A Embryonal tumor ETMR Proteomics Spine density Microtubule Neurology. Diseases of the nervous system RC346-429
Acceso en línea:	https://doaj.org/article/fafa30e3b2494779a1d5c062439e2ceb
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spelling	oai:doaj.org-article:fafa30e3b2494779a1d5c062439e2ceb2021-11-21T12:07:32ZOverexpression of Lin28A in neural progenitor cells in vivo does not lead to brain tumor formation but results in reduced spine density10.1186/s40478-021-01289-12051-5960https://doaj.org/article/fafa30e3b2494779a1d5c062439e2ceb2021-11-01T00:00:00Zhttps://doi.org/10.1186/s40478-021-01289-1https://doaj.org/toc/2051-5960Abstract LIN28A overexpression has been identified in malignant brain tumors called embryonal tumors with multilayered rosettes (ETMR) but its specific role during brain development remains largely unknown. Radial glia cells of the ventricular zone (VZ) are proposed as a cell of origin for ETMR. We asked whether an overexpression of LIN28A in such cells might affect brain development or result in the formation of brain tumors. Constitutive overexpression of LIN28A in hGFAP-cre::lsl-Lin28A (GL) mice led to a transient increase of proliferation in the cortical VZ at embryonic stages but no postnatal brain tumor formation. Postnatally, GL mice displayed a pyramidal cell layer dispersion of the hippocampus and altered spine and dendrite morphology, including reduced dendritic spine densities in the hippocampus and cortex. GL mice displayed hyperkinetic activity and differential quantitative MS-based proteomics revealed altered time dependent molecular functions regarding mRNA processing and spine morphogenesis. Phosphoproteomic analyses indicated a downregulation of mTOR pathway modulated proteins such as Map1b being involved in microtubule dynamics. In conclusion, we show that Lin28A overexpression transiently increases proliferation of neural precursor cells but it is not sufficient to drive brain tumors in vivo. In contrast, Lin28A impacts on protein abundancy patterns related to spine morphogenesis and phosphorylation levels of proteins involved in microtubule dynamics, resulting in decreased spine densities of neurons in the hippocampus and cortex as well as in altered behavior. Our work provides new insights into the role of LIN28A for neuronal morphogenesis and development and may reveal future targets for treatment of ETMR patients.Maximilian MiddelkampLisa RuckChristoph KrispPiotr SumisławskiBehnam MohammadiMatthias DottermuschValerie MeisterLukas KüsterHartmut SchlüterSabine WindhorstJulia E. NeumannBMCarticleLIN28AEmbryonal tumorETMRProteomicsSpine densityMicrotubuleNeurology. Diseases of the nervous systemRC346-429ENActa Neuropathologica Communications, Vol 9, Iss 1, Pp 1-24 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	LIN28A Embryonal tumor ETMR Proteomics Spine density Microtubule Neurology. Diseases of the nervous system RC346-429
spellingShingle	LIN28A Embryonal tumor ETMR Proteomics Spine density Microtubule Neurology. Diseases of the nervous system RC346-429 Maximilian Middelkamp Lisa Ruck Christoph Krisp Piotr Sumisławski Behnam Mohammadi Matthias Dottermusch Valerie Meister Lukas Küster Hartmut Schlüter Sabine Windhorst Julia E. Neumann Overexpression of Lin28A in neural progenitor cells in vivo does not lead to brain tumor formation but results in reduced spine density
description	Abstract LIN28A overexpression has been identified in malignant brain tumors called embryonal tumors with multilayered rosettes (ETMR) but its specific role during brain development remains largely unknown. Radial glia cells of the ventricular zone (VZ) are proposed as a cell of origin for ETMR. We asked whether an overexpression of LIN28A in such cells might affect brain development or result in the formation of brain tumors. Constitutive overexpression of LIN28A in hGFAP-cre::lsl-Lin28A (GL) mice led to a transient increase of proliferation in the cortical VZ at embryonic stages but no postnatal brain tumor formation. Postnatally, GL mice displayed a pyramidal cell layer dispersion of the hippocampus and altered spine and dendrite morphology, including reduced dendritic spine densities in the hippocampus and cortex. GL mice displayed hyperkinetic activity and differential quantitative MS-based proteomics revealed altered time dependent molecular functions regarding mRNA processing and spine morphogenesis. Phosphoproteomic analyses indicated a downregulation of mTOR pathway modulated proteins such as Map1b being involved in microtubule dynamics. In conclusion, we show that Lin28A overexpression transiently increases proliferation of neural precursor cells but it is not sufficient to drive brain tumors in vivo. In contrast, Lin28A impacts on protein abundancy patterns related to spine morphogenesis and phosphorylation levels of proteins involved in microtubule dynamics, resulting in decreased spine densities of neurons in the hippocampus and cortex as well as in altered behavior. Our work provides new insights into the role of LIN28A for neuronal morphogenesis and development and may reveal future targets for treatment of ETMR patients.
format	article
author	Maximilian Middelkamp Lisa Ruck Christoph Krisp Piotr Sumisławski Behnam Mohammadi Matthias Dottermusch Valerie Meister Lukas Küster Hartmut Schlüter Sabine Windhorst Julia E. Neumann
author_facet	Maximilian Middelkamp Lisa Ruck Christoph Krisp Piotr Sumisławski Behnam Mohammadi Matthias Dottermusch Valerie Meister Lukas Küster Hartmut Schlüter Sabine Windhorst Julia E. Neumann
author_sort	Maximilian Middelkamp
title	Overexpression of Lin28A in neural progenitor cells in vivo does not lead to brain tumor formation but results in reduced spine density
title_short	Overexpression of Lin28A in neural progenitor cells in vivo does not lead to brain tumor formation but results in reduced spine density
title_full	Overexpression of Lin28A in neural progenitor cells in vivo does not lead to brain tumor formation but results in reduced spine density
title_fullStr	Overexpression of Lin28A in neural progenitor cells in vivo does not lead to brain tumor formation but results in reduced spine density
title_full_unstemmed	Overexpression of Lin28A in neural progenitor cells in vivo does not lead to brain tumor formation but results in reduced spine density
title_sort	overexpression of lin28a in neural progenitor cells in vivo does not lead to brain tumor formation but results in reduced spine density
publisher	BMC
publishDate	2021
url	https://doaj.org/article/fafa30e3b2494779a1d5c062439e2ceb
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Overexpression of Lin28A in neural progenitor cells in vivo does not lead to brain tumor formation but results in reduced spine density

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