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Nat Neurosci. 2007 Jan;10(1):77-86. Epub 2006 Dec 10.

Essential function of HIPK2 in TGFbeta-dependent survival of midbrain dopamine neurons.

Author information

1
Department of Pathology, University of California San Francisco, 505 Parnassus Avenue, San Francisco, CA 94143, USA.

Abstract

Transforming growth factor beta (TGFbeta) is a potent trophic factor for midbrain dopamine (DA) neurons, but its in vivo function and signaling mechanisms are not entirely understood. We show that the transcriptional cofactor homeodomain interacting protein kinase 2 (HIPK2) is required for the TGFbeta-mediated survival of mouse DA neurons. The targeted deletion of Hipk2 has no deleterious effect on the neurogenesis of DA neurons, but leads to a selective loss of these neurons that is due to increased apoptosis during programmed cell death. As a consequence, Hipk2(-/-) mutants show an array of psychomotor abnormalities. The function of HIPK2 depends on its interaction with receptor-regulated Smads to activate TGFbeta target genes. In support of this notion, DA neurons from Hipk2(-/-) mutants fail to survive in the presence of TGFbeta3 and Tgfbeta3(-/-) mutants show DA neuron abnormalities similar to those seen in Hipk2(-/-) mutants. These data underscore the importance of the TGFbeta-Smad-HIPK2 pathway in the survival of DA neurons and its potential as a therapeutic target for promoting DA neuron survival during neurodegeneration.

PMID:
17159989
PMCID:
PMC3578579
DOI:
10.1038/nn1816
[Indexed for MEDLINE]
Free PMC Article

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