title: NF1 regulation of RAS/ERK signaling is required for appropriate granule neuron progenitor expansion and migration in cerebellar development.
abstract: Cerebellar development is regulated by a coordinated spatiotemporal interplay between granule neuron progenitors (GNPs), Purkinje neurons, and glia. Abnormal development can trigger motor deficits, and more recent data indicate important roles in aspects of memory, behavior, and autism spectrum disorders (ASDs). Germline mutation in the NF1 tumor suppressor gene underlies Neurofibromatosis type 1, a complex disease that enhances susceptibility to certain cancers and neurological disorders, including intellectual deficits and ASD. The NF1 gene encodes for neurofibromin, a RAS GTPase-activating protein, and thus negatively regulates the RAS signaling pathway. Here, using mouse models to direct conditional NF1 ablation in either embryonic cerebellar progenitors or neonatal GNPs, we show that neurofibromin is required for appropriate development of cerebellar folia layering and structure. Remarkably, neonatal administration of inhibitors of the ERK pathway reversed the morphological defects. Thus, our findings establish a critical cell-autonomous role for the NF1-RAS-ERK pathway in the appropriate regulation of cerebellar development and provide a basis for using neonatal ERK inhibitor-based therapies to treat NF1-induced cerebellar disorders.
authors.affiliation: Department of Developmental Biology, Kent Waldrep Foundation Center for Research on Nerve Growth and Regeneration, University of Texas Southwestern Medical School, Dallas, Texas 75390, USA.
authors.forename: Efrain
authors.initials: E
authors.lastname: Sanchez-Ortiz
authors.affiliation: Department of Developmental Biology, Kent Waldrep Foundation Center for Research on Nerve Growth and Regeneration, University of Texas Southwestern Medical School, Dallas, Texas 75390, USA.
authors.forename: Woosung
authors.initials: W
authors.lastname: Cho
authors.affiliation: Department of Developmental Biology, Kent Waldrep Foundation Center for Research on Nerve Growth and Regeneration, University of Texas Southwestern Medical School, Dallas, Texas 75390, USA.
authors.forename: Inga
authors.initials: I
authors.lastname: Nazarenko
authors.affiliation: Department of Developmental Biology, Kent Waldrep Foundation Center for Research on Nerve Growth and Regeneration, University of Texas Southwestern Medical School, Dallas, Texas 75390, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Mo
authors.affiliation: Department of Developmental Biology, Kent Waldrep Foundation Center for Research on Nerve Growth and Regeneration, University of Texas Southwestern Medical School, Dallas, Texas 75390, USA luis.parada@utsouthwestern.edu chenjian2014@suda.edu.cn.
authors.forename: Jian
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Developmental Biology, Kent Waldrep Foundation Center for Research on Nerve Growth and Regeneration, University of Texas Southwestern Medical School, Dallas, Texas 75390, USA luis.parada@utsouthwestern.edu chenjian2014@suda.edu.cn.
authors.forename: Luis F
authors.initials: LF
authors.lastname: Parada
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D002531:Cerebellum / Q000166:cytology / Q000196:embryology* / Q000254:growth & development; D017353:Gene Deletion; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D025542:Neurofibromin 1 / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D018631:ras Proteins / Q000502:physiology*
chemical_list: D025542:Neurofibromin 1; D047428:Protein Kinase Inhibitors; D018631:ras Proteins
keywords: CNS development; NF1; Neurofibromatosis type 1; barrel cortex; cerebellum; granule neuron progenitor