Transient inhibition of the ERK pathway prevents cerebellar developmental defects and improves long-term motor functions in murine models of neurofibromatosis type 1

Transient inhibition of the ERK pathway prevents cerebellar developmental defects and improves long-term motor functions in murine models of neurofibromatosis type 1

Individuals with neurofibromatosis type 1 (NF1) frequently exhibit cognitive and motor impairments and characteristics of autism. The cerebellum plays a critical role in motor control, cognition, and social interaction, suggesting that cerebellar defects likely contribute to NF1-associated neurodeve...

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Main Authors: Kim, Edward, Wang, Yuan, Kim, Sun-Jung, Bornhorst, Miriam, Jecrois, Emmanuelle S, Anthony, Todd E, Wang, Chenran, Li, Yi E, Guan, Jun-Lin, Murphy, Geoffrey G, Zhu, Yuan
Format: Online
Language:English
Published: eLife Sciences Publications, Ltd 2014
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4297949/
id pubmed-4297949
recordtype oai_dc
spelling pubmed-42979492015-01-29 Transient inhibition of the ERK pathway prevents cerebellar developmental defects and improves long-term motor functions in murine models of neurofibromatosis type 1 Kim, Edward Wang, Yuan Kim, Sun-Jung Bornhorst, Miriam Jecrois, Emmanuelle S Anthony, Todd E Wang, Chenran Li, Yi E Guan, Jun-Lin Murphy, Geoffrey G Zhu, Yuan Developmental Biology and Stem Cells Individuals with neurofibromatosis type 1 (NF1) frequently exhibit cognitive and motor impairments and characteristics of autism. The cerebellum plays a critical role in motor control, cognition, and social interaction, suggesting that cerebellar defects likely contribute to NF1-associated neurodevelopmental disorders. Here we show that Nf1 inactivation during early, but not late stages of cerebellar development, disrupts neuronal lamination, which is partially caused by overproduction of glia and subsequent disruption of the Bergmann glia (BG) scaffold. Specific Nf1 inactivation in glutamatergic neuronal precursors causes premature differentiation of granule cell (GC) precursors and ectopic production of unipolar brush cells (UBCs), indirectly disrupting neuronal migration. Transient MEK inhibition during a neonatal window prevents cerebellar developmental defects and improves long-term motor performance of Nf1-deficient mice. This study reveals essential roles of Nf1 in GC/UBC migration by generating correct numbers of glia and controlling GC/UBC fate-specification/differentiation, identifying a therapeutic prevention strategy for multiple NF1-associcated developmental abnormalities. eLife Sciences Publications, Ltd 2014-12-23 /pmc/articles/PMC4297949/ /pubmed/25535838 http://dx.doi.org/10.7554/eLife.05151 Text en © 2014, Kim et al http://creativecommons.org/licenses/by/4.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Kim, Edward
Wang, Yuan
Kim, Sun-Jung
Bornhorst, Miriam
Jecrois, Emmanuelle S
Anthony, Todd E
Wang, Chenran
Li, Yi E
Guan, Jun-Lin
Murphy, Geoffrey G
Zhu, Yuan
spellingShingle Kim, Edward
Wang, Yuan
Kim, Sun-Jung
Bornhorst, Miriam
Jecrois, Emmanuelle S
Anthony, Todd E
Wang, Chenran
Li, Yi E
Guan, Jun-Lin
Murphy, Geoffrey G
Zhu, Yuan
Transient inhibition of the ERK pathway prevents cerebellar developmental defects and improves long-term motor functions in murine models of neurofibromatosis type 1
author_facet Kim, Edward
Wang, Yuan
Kim, Sun-Jung
Bornhorst, Miriam
Jecrois, Emmanuelle S
Anthony, Todd E
Wang, Chenran
Li, Yi E
Guan, Jun-Lin
Murphy, Geoffrey G
Zhu, Yuan
author_sort Kim, Edward
title Transient inhibition of the ERK pathway prevents cerebellar developmental defects and improves long-term motor functions in murine models of neurofibromatosis type 1
title_short Transient inhibition of the ERK pathway prevents cerebellar developmental defects and improves long-term motor functions in murine models of neurofibromatosis type 1
title_full Transient inhibition of the ERK pathway prevents cerebellar developmental defects and improves long-term motor functions in murine models of neurofibromatosis type 1
title_fullStr Transient inhibition of the ERK pathway prevents cerebellar developmental defects and improves long-term motor functions in murine models of neurofibromatosis type 1
title_full_unstemmed Transient inhibition of the ERK pathway prevents cerebellar developmental defects and improves long-term motor functions in murine models of neurofibromatosis type 1
title_sort transient inhibition of the erk pathway prevents cerebellar developmental defects and improves long-term motor functions in murine models of neurofibromatosis type 1
description Individuals with neurofibromatosis type 1 (NF1) frequently exhibit cognitive and motor impairments and characteristics of autism. The cerebellum plays a critical role in motor control, cognition, and social interaction, suggesting that cerebellar defects likely contribute to NF1-associated neurodevelopmental disorders. Here we show that Nf1 inactivation during early, but not late stages of cerebellar development, disrupts neuronal lamination, which is partially caused by overproduction of glia and subsequent disruption of the Bergmann glia (BG) scaffold. Specific Nf1 inactivation in glutamatergic neuronal precursors causes premature differentiation of granule cell (GC) precursors and ectopic production of unipolar brush cells (UBCs), indirectly disrupting neuronal migration. Transient MEK inhibition during a neonatal window prevents cerebellar developmental defects and improves long-term motor performance of Nf1-deficient mice. This study reveals essential roles of Nf1 in GC/UBC migration by generating correct numbers of glia and controlling GC/UBC fate-specification/differentiation, identifying a therapeutic prevention strategy for multiple NF1-associcated developmental abnormalities.
publisher eLife Sciences Publications, Ltd
publishDate 2014
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4297949/
_version_ 1613177850130595840

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