Transient inhibition of the ERK pathway prevents cerebellar developmental defects and improves long-term motor functions in murine models of neurofibromatosis type 1
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Dec 23, 2014
- Source ID
- 10.7554/elife.05151
Entities
People
- Chenran Wang
- Edward Kim
- Emmanuelle S. Jecrois
- Geoffrey G. Murphy
- Jun-lin Guan
- Miriam Bornhorst
- Sun-jung Kim
- Todd E Anthony
- Yi E Li
- Yuan Wang
- Yuan Zhu
Organizations
- National Cancer Institute
- National Institutes of Health
- The Rockefeller University
- United States Department of Defense
- University of Cincinnati
- University of Michigan