Essential function of HIPK2 in TGFbeta-dependent survival of midbrain dopamine neurons.
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.
Zhang
Jiasheng
J
Department of Pathology, University of California San Francisco, 505 Parnassus Avenue, San Francisco, CA 94143, USA.
Pho
Vanee
V
Bonasera
Stephen J
SJ
Holtzman
Jed
J
Tang
Amy T
AT
Hellmuth
Joanna
J
Tang
Siuwah
S
Janak
Patricia H
PH
Tecott
Laurence H
LH
Huang
Eric J
EJ
D000661:Amphetamine / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000502:physiology; D001522:Behavior, Animal; D001552:Benzazepines / Q000494:pharmacology; D064026:Calbindins; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002352:Carrier Proteins / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology; D004622:Embryo, Mammalian; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D018398:Homeodomain Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D008636:Mesencephalon / Q000166:cytology*; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000502:physiology*; D064030:S100 Calcium Binding Protein G; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D001552:Benzazepines; D064026:Calbindins; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D000697:Central Nervous System Stimulants; D018491:Dopamine Agonists; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D064030:S100 Calcium Binding Protein G; D016212:Transforming Growth Factor beta; C067113:SK&F 81297; D000661:Amphetamine; D014446:Tyrosine 3-Monooxygenase; C492003:Hipk2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D004298:Dopamine