title: 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.
authors.affiliation: Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States.
authors.forename: Edward
authors.initials: E
authors.lastname: Kim
authors.affiliation: Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States.
authors.forename: Sun-Jung
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States.
authors.forename: Miriam
authors.initials: M
authors.lastname: Bornhorst
authors.affiliation: Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States.
authors.forename: Emmanuelle S
authors.initials: ES
authors.lastname: Jecrois
authors.affiliation: Laboratory of Molecular Biology, Rockefeller University, New York, United States.
authors.forename: Todd E
authors.initials: TE
authors.lastname: Anthony
authors.affiliation: Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, United States.
authors.forename: Chenran
authors.initials: C
authors.lastname: Wang
authors.affiliation: Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States.
authors.forename: Yi E
authors.initials: YE
authors.lastname: Li
authors.affiliation: Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States.
authors.forename: Jun-Lin
authors.initials: JL
authors.lastname: Guan
authors.affiliation: Molecular and Behavioral Neuroscience Institute, University of Michigan Medical School, Ann Arbor, United States.
authors.forename: Geoffrey G
authors.initials: GG
authors.lastname: Murphy
authors.affiliation: Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhu
mesh_terms: D000483:Alleles; D000818:Animals; D001253:Astrocytes / Q000473:pathology; D049109:Cell Proliferation; D002531:Cerebellum / Q000201:enzymology / Q000473:pathology; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020868:Gene Silencing; D016514:Genes, Neurofibromatosis 1; D007858:Learning; D051379:Mice; D017253:Neurofibromatoses / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology*; D009474:Neurons / Q000473:pathology; D011597:Psychomotor Performance
chemical_list: D048049:Extracellular Signal-Regulated MAP Kinases
keywords: bergmann glial cells; cerebellum; developmental biology; granule cells; mouse; neurofibromatosis type 1; stem cells; tumor suppressor gene; unipolar brush cells