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

Jiasheng Zhang; Vanee Pho; Stephen J. Bonasera; Jed Holzmann; Amy T. Tang; Joanna Hellmuth; Siuwah Tang; Patricia H. Janak; Laurence H. Tecott; Eric J. Huang

doi:10.1038/nn1816

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

Jiasheng Zhang
, Vanee Pho
, Stephen J. Bonasera
, Jed Holzmann
, Amy T. Tang
, Joanna Hellmuth
, Siuwah Tang
, Patricia H. Janak
, Laurence H. Tecott
, Eric J. Huang

Research output: Contribution to journal › Article › peer-review

Abstract

Transforming growth factor beta (TGFβ) 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 TGFβ-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 TGFβ target genes. In support of this notion, DA neurons from Hipk2^-/- mutants fail to survive in the presence of TGFβ3 and Tgfβ3^-/- mutants show DA neuron abnormalities similar to those seen in Hipk2^-/- mutants. These data underscore the importance of the TGFβ-Smad-HIPK2 pathway in the survival of DA neurons and its potential as a therapeutic target for promoting DA neuron survival during neurodegeneration.

Original language	English (US)
Pages (from-to)	77-86
Number of pages	10
Journal	Nature neuroscience
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/nn1816
State	Published - Jan 2007
Externally published	Yes

ASJC Scopus subject areas

General Neuroscience

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@article{ce25d7deb4df4a1eaeff95a60a1bef6a,

title = "Essential function of HIPK2 in TGFβ-dependent survival of midbrain dopamine neurons",

abstract = "Transforming growth factor beta (TGFβ) 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 TGFβ-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 TGFβ target genes. In support of this notion, DA neurons from Hipk2-/- mutants fail to survive in the presence of TGFβ3 and Tgfβ3-/- mutants show DA neuron abnormalities similar to those seen in Hipk2-/- mutants. These data underscore the importance of the TGFβ-Smad-HIPK2 pathway in the survival of DA neurons and its potential as a therapeutic target for promoting DA neuron survival during neurodegeneration.",

author = "Jiasheng Zhang and Vanee Pho and Bonasera, \{Stephen J.\} and Jed Holzmann and Tang, \{Amy T.\} and Joanna Hellmuth and Siuwah Tang and Janak, \{Patricia H.\} and Tecott, \{Laurence H.\} and Huang, \{Eric J.\}",

note = "Funding Information: We thank L.F. Reichardt and S. Pleasure for comments on the manuscript. Special thanks to J. Siegenthaler for TGFb1 antibody, D.J. Anderson for Ngn2 antibody, R. Akhurst for Tgfb1 mutants, T. Doestchman for Tgfb3 mutants, D. Di Monte for dopamine HPLC assays, T. Wyss-Coray for Smads and SBE-luciferase plasmids, A. Buckley for characterizing HIPK2LacZ expression, S. Ku for mutant HIPK2 plasmids, C. Wong for histology and G. Wei for generating Hipk2 mutants. V.P. was supported in part by a postdoctoral fellowship from the American Parkinson Disease Association. This work was supported by grants from the National Institute of Neurological Disorders and Stroke (NS44223 and NS48393), a Pilot Project Grant from the University of California San Francisco (UCSF) Alzheimer{\textquoteright}s Disease Research Center (AG23501), Veteran{\textquoteright}s Administration Merit Review, Presidential Early Career Award for Scientists and Engineers, National Parkinson Foundation, and The Michael J. Fox Foundation for Parkinson{\textquoteright}s Research to E.J.H., funds from the state of California for medical Funding Information: research on alcohol and drug abuse through UCSF to P.H.J., and grants from the US National Institutes of Health to P.H.J. and L.H.T.",

year = "2007",

month = jan,

doi = "10.1038/nn1816",

language = "English (US)",

volume = "10",

pages = "77--86",

journal = "Nature neuroscience",

issn = "1097-6256",

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T1 - Essential function of HIPK2 in TGFβ-dependent survival of midbrain dopamine neurons

AU - Zhang, Jiasheng

AU - Pho, Vanee

AU - Bonasera, Stephen J.

AU - Holzmann, Jed

AU - Tang, Amy T.

AU - Hellmuth, Joanna

AU - Tang, Siuwah

AU - Janak, Patricia H.

AU - Tecott, Laurence H.

AU - Huang, Eric J.

N1 - Funding Information: We thank L.F. Reichardt and S. Pleasure for comments on the manuscript. Special thanks to J. Siegenthaler for TGFb1 antibody, D.J. Anderson for Ngn2 antibody, R. Akhurst for Tgfb1 mutants, T. Doestchman for Tgfb3 mutants, D. Di Monte for dopamine HPLC assays, T. Wyss-Coray for Smads and SBE-luciferase plasmids, A. Buckley for characterizing HIPK2LacZ expression, S. Ku for mutant HIPK2 plasmids, C. Wong for histology and G. Wei for generating Hipk2 mutants. V.P. was supported in part by a postdoctoral fellowship from the American Parkinson Disease Association. This work was supported by grants from the National Institute of Neurological Disorders and Stroke (NS44223 and NS48393), a Pilot Project Grant from the University of California San Francisco (UCSF) Alzheimer’s Disease Research Center (AG23501), Veteran’s Administration Merit Review, Presidential Early Career Award for Scientists and Engineers, National Parkinson Foundation, and The Michael J. Fox Foundation for Parkinson’s Research to E.J.H., funds from the state of California for medical Funding Information: research on alcohol and drug abuse through UCSF to P.H.J., and grants from the US National Institutes of Health to P.H.J. and L.H.T.

PY - 2007/1

Y1 - 2007/1

N2 - Transforming growth factor beta (TGFβ) 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 TGFβ-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 TGFβ target genes. In support of this notion, DA neurons from Hipk2-/- mutants fail to survive in the presence of TGFβ3 and Tgfβ3-/- mutants show DA neuron abnormalities similar to those seen in Hipk2-/- mutants. These data underscore the importance of the TGFβ-Smad-HIPK2 pathway in the survival of DA neurons and its potential as a therapeutic target for promoting DA neuron survival during neurodegeneration.

AB - Transforming growth factor beta (TGFβ) 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 TGFβ-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 TGFβ target genes. In support of this notion, DA neurons from Hipk2-/- mutants fail to survive in the presence of TGFβ3 and Tgfβ3-/- mutants show DA neuron abnormalities similar to those seen in Hipk2-/- mutants. These data underscore the importance of the TGFβ-Smad-HIPK2 pathway in the survival of DA neurons and its potential as a therapeutic target for promoting DA neuron survival during neurodegeneration.

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DO - 10.1038/nn1816

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AN - SCOPUS:33845889727

SN - 1097-6256

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SP - 77

EP - 86

JO - Nature neuroscience

JF - Nature neuroscience

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ER -

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

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