Targeted deletion of the mitogen-activated protein kinase kinase 4 gene in the nervous system causes severe brain developmental defects and premature death

Xin Wang, Bagirathy Nadarajah, Andrew C. Robinson, Barry W. McColl, Jia Wei Jin, Federico Dajas-Bailador, Raymond P. Boot-Handford, Cathy Tournier

    Research output: Contribution to journalArticlepeer-review

    Abstract

    The c-Jun NH2-terminal protein kinase (JNK) is a mitogen-activated protein kinase (MAPK) involved in the regulation of various physiological processes. Its activity is increased upon phosphorylation by the MAPK kinases MKK4 and MKK7. The early embryonic death of mice lacking an mkk4 or mkk7 gene has provided genetic evidence that MKK4 and MKK7 have nonredundant functions in vivo. To elucidate the physiological role of MKK4, we generated a novel mouse model in which the mkk4 gene could be specifically deleted in the brain. At birth, the mutant mice were indistinguishable from their control littermates, but they stopped growing a few days later and died prematurely, displaying severe neurological defects. Decreased JNK activity in the absence of MKK4 correlated with impaired phosphorylation of a subset of physiologically relevant JNK substrates and with altered gene expression. These defects resulted in the misalignment of the Purkinje cells in the cerebellum and delayed radial migration in the cerebral cortex. Together, our data demonstrate for the first time that MKK4 is an essential activator of JNK required for the normal development of the brain. Copyright © 2007, American Society for Microbiology. All Rights Reserved.
    Original languageEnglish
    Pages (from-to)7935-7946
    Number of pages11
    JournalMolecular and Cellular Biology
    Volume27
    Issue number22
    DOIs
    Publication statusPublished - Nov 2007

    Fingerprint

    Dive into the research topics of 'Targeted deletion of the mitogen-activated protein kinase kinase 4 gene in the nervous system causes severe brain developmental defects and premature death'. Together they form a unique fingerprint.

    Cite this