NF1 regulation of RAS/ERK signaling is required for appropriate granule neuron progenitor expansion and migration in cerebellar development

Efrain Sanchez-Ortiz, Woosung Cho, Inga Nazarenko, Wei Mo, Jian Chen, Luis F. Parada

Research output: Contribution to journalArticle

22 Scopus citations


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 mousemodels 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.

Original languageEnglish (US)
Pages (from-to)2407-2420
Number of pages14
JournalGenes and Development
Issue number21
Publication statusPublished - Nov 1 2014



  • Barrel cortex
  • Cerebellum
  • CNS development
  • Granule neuron progenitor
  • Neurofibromatosis type 1
  • NF1

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology
  • Medicine(all)

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