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

19 Citations (Scopus)

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 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
Volume28
Issue number21
DOIs
StatePublished - Nov 1 2014

Fingerprint

Neurofibromin 1
GTPase-Activating Proteins
Cerebellar Diseases
Neurons
Neurofibromatosis 1
Germ-Line Mutation
MAP Kinase Signaling System
Purkinje Cells
Disease Susceptibility
Nervous System Diseases
Tumor Suppressor Genes
Neuroglia
Genes
Neoplasms
Autism Spectrum Disorder
Therapeutics

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology
  • Medicine(all)

Cite this

NF1 regulation of RAS/ERK signaling is required for appropriate granule neuron progenitor expansion and migration in cerebellar development. / Sanchez-Ortiz, Efrain; Cho, Woosung; Nazarenko, Inga; Mo, Wei; Chen, Jian; Parada, Luis F.

In: Genes and Development, Vol. 28, No. 21, 01.11.2014, p. 2407-2420.

Research output: Contribution to journalArticle

Sanchez-Ortiz, Efrain ; Cho, Woosung ; Nazarenko, Inga ; Mo, Wei ; Chen, Jian ; Parada, Luis F. / NF1 regulation of RAS/ERK signaling is required for appropriate granule neuron progenitor expansion and migration in cerebellar development. In: Genes and Development. 2014 ; Vol. 28, No. 21. pp. 2407-2420.
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