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

Nat Neurosci. 2007 Jan;10(1):77-86. doi: 10.1038/nn1816. Epub 2006 Dec 10.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amphetamine / pharmacology
  • Analysis of Variance
  • Animals
  • Animals, Newborn
  • Apoptosis / physiology
  • Behavior, Animal
  • Benzazepines / pharmacology
  • Calbindins
  • Calcium-Binding Proteins / metabolism
  • Carrier Proteins / physiology*
  • Cell Survival / physiology
  • Cells, Cultured
  • Central Nervous System Stimulants / pharmacology
  • Dopamine / metabolism*
  • Dopamine Agonists / pharmacology
  • Embryo, Mammalian
  • Gene Expression Regulation, Developmental / physiology*
  • Homeodomain Proteins / metabolism
  • Immunohistochemistry
  • Mesencephalon / cytology*
  • Mice
  • Mice, Knockout
  • Motor Activity / drug effects
  • Motor Activity / genetics
  • Nerve Tissue Proteins / metabolism
  • Neurons / physiology*
  • Protein-Serine-Threonine Kinases / deficiency
  • Protein-Serine-Threonine Kinases / physiology*
  • S100 Calcium Binding Protein G
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / physiology*
  • Tyrosine 3-Monooxygenase / metabolism

Substances

  • Benzazepines
  • Calbindins
  • Calcium-Binding Proteins
  • Carrier Proteins
  • Central Nervous System Stimulants
  • Dopamine Agonists
  • Homeodomain Proteins
  • Nerve Tissue Proteins
  • S100 Calcium Binding Protein G
  • Transforming Growth Factor beta
  • SK&F 81297
  • Amphetamine
  • Tyrosine 3-Monooxygenase
  • Hipk2 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Dopamine