Transient inhibition of the ERK pathway prevents cerebellar developmental defects and improves long-term motor functions in murine models of neurofibromatosis type 1
- University of Michigan Medical School, United States
- Children's National Medical Center, United States
- Rockefeller University, United States
- University of Cincinnati College of Medicine, United States
Abstract
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.
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Ethics
Animal experimentation: All mice in this study were cared for according to the guidelines that were approved by the Animal Care and Use Committees of the University of Michigan at Ann Arbor, MI and the Children's National Medical Center in Washington, DC. The approved protocol number at the University of Michigan is PRO00004481. The project (ID# 30001543) was approved by the IACUC (Protocol#: 309-13-09) of the Children's National Medical Center at Washington.
Copyright
© 2014, Kim et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Transient inhibition of the ERK pathway prevents cerebellar developmental defects and improves long-term motor functions in murine models of neurofibromatosis type 1
eLife 3:e05151.
https://doi.org/10.7554/eLife.05151
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