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