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NF1 regulation of RAS/ERK signaling is required for appropriate granule neuron progenitor expansion and migration in cerebellar development

Cerebellar development is regulated by a coordinated spatiotemporal interplay between granule neuron progenitors (GNPs), Purkinje neurons, and glia. Abnormal development can trigger motor deficits, and more recent data indicate important roles in aspects of memory, behavior, and autism spectrum diso...

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Autores principales: Sanchez-Ortiz, Efrain, Cho, Woosung, Nazarenko, Inga, Mo, Wei, Chen, Jian, Parada, Luis F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4215185/
https://www.ncbi.nlm.nih.gov/pubmed/25367036
http://dx.doi.org/10.1101/gad.246603.114
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author Sanchez-Ortiz, Efrain
Cho, Woosung
Nazarenko, Inga
Mo, Wei
Chen, Jian
Parada, Luis F.
author_facet Sanchez-Ortiz, Efrain
Cho, Woosung
Nazarenko, Inga
Mo, Wei
Chen, Jian
Parada, Luis F.
author_sort Sanchez-Ortiz, Efrain
collection PubMed
description Cerebellar development is regulated by a coordinated spatiotemporal interplay between granule neuron progenitors (GNPs), Purkinje neurons, and glia. Abnormal development can trigger motor deficits, and more recent data indicate important roles in aspects of memory, behavior, and autism spectrum disorders (ASDs). Germline mutation in the NF1 tumor suppressor gene underlies Neurofibromatosis type 1, a complex disease that enhances susceptibility to certain cancers and neurological disorders, including intellectual deficits and ASD. The NF1 gene encodes for neurofibromin, a RAS GTPase-activating protein, and thus negatively regulates the RAS signaling pathway. Here, using mouse models to direct conditional NF1 ablation in either embryonic cerebellar progenitors or neonatal GNPs, we show that neurofibromin is required for appropriate development of cerebellar folia layering and structure. Remarkably, neonatal administration of inhibitors of the ERK pathway reversed the morphological defects. Thus, our findings establish a critical cell-autonomous role for the NF1–RAS–ERK pathway in the appropriate regulation of cerebellar development and provide a basis for using neonatal ERK inhibitor-based therapies to treat NF1-induced cerebellar disorders.
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spelling pubmed-42151852015-05-01 NF1 regulation of RAS/ERK signaling is required for appropriate granule neuron progenitor expansion and migration in cerebellar development Sanchez-Ortiz, Efrain Cho, Woosung Nazarenko, Inga Mo, Wei Chen, Jian Parada, Luis F. Genes Dev Research Paper Cerebellar development is regulated by a coordinated spatiotemporal interplay between granule neuron progenitors (GNPs), Purkinje neurons, and glia. Abnormal development can trigger motor deficits, and more recent data indicate important roles in aspects of memory, behavior, and autism spectrum disorders (ASDs). Germline mutation in the NF1 tumor suppressor gene underlies Neurofibromatosis type 1, a complex disease that enhances susceptibility to certain cancers and neurological disorders, including intellectual deficits and ASD. The NF1 gene encodes for neurofibromin, a RAS GTPase-activating protein, and thus negatively regulates the RAS signaling pathway. Here, using mouse models to direct conditional NF1 ablation in either embryonic cerebellar progenitors or neonatal GNPs, we show that neurofibromin is required for appropriate development of cerebellar folia layering and structure. Remarkably, neonatal administration of inhibitors of the ERK pathway reversed the morphological defects. Thus, our findings establish a critical cell-autonomous role for the NF1–RAS–ERK pathway in the appropriate regulation of cerebellar development and provide a basis for using neonatal ERK inhibitor-based therapies to treat NF1-induced cerebellar disorders. Cold Spring Harbor Laboratory Press 2014-11-01 /pmc/articles/PMC4215185/ /pubmed/25367036 http://dx.doi.org/10.1101/gad.246603.114 Text en © 2014 Sanchez-Ortiz et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Research Paper
Sanchez-Ortiz, Efrain
Cho, Woosung
Nazarenko, Inga
Mo, Wei
Chen, Jian
Parada, Luis F.
NF1 regulation of RAS/ERK signaling is required for appropriate granule neuron progenitor expansion and migration in cerebellar development
title NF1 regulation of RAS/ERK signaling is required for appropriate granule neuron progenitor expansion and migration in cerebellar development
title_full NF1 regulation of RAS/ERK signaling is required for appropriate granule neuron progenitor expansion and migration in cerebellar development
title_fullStr NF1 regulation of RAS/ERK signaling is required for appropriate granule neuron progenitor expansion and migration in cerebellar development
title_full_unstemmed NF1 regulation of RAS/ERK signaling is required for appropriate granule neuron progenitor expansion and migration in cerebellar development
title_short NF1 regulation of RAS/ERK signaling is required for appropriate granule neuron progenitor expansion and migration in cerebellar development
title_sort nf1 regulation of ras/erk signaling is required for appropriate granule neuron progenitor expansion and migration in cerebellar development
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4215185/
https://www.ncbi.nlm.nih.gov/pubmed/25367036
http://dx.doi.org/10.1101/gad.246603.114
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