Essential role of B-Raf in oligodendrocyte maturation and myelination during postnatal central nervous system development

Autor(en)

Gergana Galabova-Kovacs, Federica Catalanotti, Dana Matzen, Gloria Reyes, Jürgen Zezula, Ruth Herbst, Alcino Silva, Ingrid Walter, Manuela Baccarini

Abstrakt

Mutations in the extracellular signal-regulated kinase (ERK) pathway, particularly in the mitogen-activated protein kinase/ERK kinase (MEK) activator B-Raf, are associated with human tumorigenesis and genetic disorders. Hence, B-Raf is a prime target for molecule-based therapies, and understanding its essential biological functions is crucial for their success. B-Raf is expressed preferentially in cells of neuronal origin. Here, we show that in mice, conditional ablation of B-Raf in neuronal precursors leads to severe dysmyelination, defective oligodendrocyte differentiation, and reduced ERK activation in brain. Both B-Raf ablation and chemical inhibition of MEK impair oligodendrocyte differentiation in vitro. In glial cell cultures, we find B-Raf in a complex with MEK, Raf-1, and kinase suppressor of Ras. In B-Raf¿deficient cells, more Raf-1 is recruited to MEK, yet MEK/ERK phosphorylation is impaired. These data define B-Raf as the rate-limiting MEK/ERK activator in oligodendrocyte differentiation and myelination and have implications for the design and use of Raf inhibitors.

Organisation(en)

Department für Mikrobiologie, Immunbiologie und Genetik

Externe Organisation(en)

Medizinische Universität Wien, University of California, Los Angeles, Veterinärmedizinische Universität Wien

Journal

The Journal of Cell Biology (JCB)

Band

180

Seiten

947-955

Anzahl der Seiten

9

ISSN

0021-9525

Publikationsdatum

2008

Peer-reviewed

Ja

ÖFOS 2012

106013 Genetik, 106023 Molekularbiologie, 301904 Krebsforschung, 301114 Zellbiologie

Sustainable Development Goals

SDG 3 – Gesundheit und Wohlergehen

Link zum Portal

https://ucrisportal.univie.ac.at/de/publications/essential-role-of-braf-in-oligodendrocyte-maturation-and-myelination-during-postnatal-central-nervous-system-development(fc176377-3100-45ee-96c0-8a31236198fa).html