Transient inhibition of the ERK pathway prevents cerebellar developmental defects and improves long-term motor functions in murine models of neurofibromatosis type 1
Edward Kim,
Yuan Wang,
Sun-Jung Kim,
Miriam Bornhorst,
Emmanuelle S Jecrois,
Todd E Anthony,
Chenran Wang,
Yi E Li,
Jun-Lin Guan,
Geoffrey G Murphy,
Yuan Zhu
Affiliations
Edward Kim
Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States
Yuan Wang
Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States; Gilbert Family Neurofibromatosis Institute, Center for Cancer and Immunology Research and Center for Neuroscience Research, Children's National Medical Center, Washington, United States; Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, United States
Sun-Jung Kim
Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States; Gilbert Family Neurofibromatosis Institute, Center for Cancer and Immunology Research and Center for Neuroscience Research, Children's National Medical Center, Washington, United States
Miriam Bornhorst
Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States; Gilbert Family Neurofibromatosis Institute, Center for Cancer and Immunology Research and Center for Neuroscience Research, Children's National Medical Center, Washington, United States; Division of Hematology and Oncology, Department of Pediatrics, Mott Children’s Hospital, University of Michigan, Ann Arbor, United States
Emmanuelle S Jecrois
Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States; Gilbert Family Neurofibromatosis Institute, Center for Cancer and Immunology Research and Center for Neuroscience Research, Children's National Medical Center, Washington, United States
Todd E Anthony
Laboratory of Molecular Biology, Rockefeller University, New York, United States
Chenran Wang
Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, United States
Yi E Li
Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States
Jun-Lin Guan
Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States; Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, United States
Geoffrey G Murphy
Molecular and Behavioral Neuroscience Institute, University of Michigan Medical School, Ann Arbor, United States; Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States
Yuan Zhu
Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States; Gilbert Family Neurofibromatosis Institute, Center for Cancer and Immunology Research and Center for Neuroscience Research, Children's National Medical Center, Washington, United States; Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, United States
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.
