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Interaction of Brn3a and HIPK2 mediates transcriptional repression of sensory neuron survival.

Wiggins AK, Wei G, Doxakis E, Wong C, Tang AA, Zang K, Luo EJ, Neve RL, Reichardt LF, Huang EJ - J. Cell Biol. (2004)

Bottom Line: Overexpression of HIPK2 induces apoptosis in cultured sensory neurons.Conversely, targeted deletion of HIPK2 leads to increased expression of Brn3a, TrkA, and Bcl-xL, reduced apoptosis and increases in neuron numbers in the trigeminal ganglion.Together, these data indicate that HIPK2, through regulation of Brn3a-dependent gene expression, is a critical component in the transcriptional machinery that controls sensory neuron survival.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, University of California San Francisco, San Francisco, CA 94143, USA.

ABSTRACT
The Pit1-Oct1-Unc86 domain (POU domain) transcription factor Brn3a controls sensory neuron survival by regulating the expression of Trk receptors and members of the Bcl-2 family. Loss of Brn3a leads to a dramatic increase in apoptosis and severe loss of neurons in sensory ganglia. Although recent evidence suggests that Brn3a-mediated transcription can be modified by additional cofactors, the exact mechanisms are not known. Here, we report that homeodomain interacting protein kinase 2 (HIPK2) is a pro-apoptotic transcriptional cofactor that suppresses Brn3a-mediated gene expression. HIPK2 interacts with Brn3a, promotes Brn3a binding to DNA, but suppresses Brn3a-dependent transcription of brn3a, trkA, and bcl-xL. Overexpression of HIPK2 induces apoptosis in cultured sensory neurons. Conversely, targeted deletion of HIPK2 leads to increased expression of Brn3a, TrkA, and Bcl-xL, reduced apoptosis and increases in neuron numbers in the trigeminal ganglion. Together, these data indicate that HIPK2, through regulation of Brn3a-dependent gene expression, is a critical component in the transcriptional machinery that controls sensory neuron survival.

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Proposed model for Brn3a and HIPK2 in transcriptional control of gene expression in sensory neurons. (A) HIPK2 is a transcriptional corepressor for Brn3a-mediated gene expression. HIPK2 interacts with Brn3a and suppresses Brn3a auto-regulatory activity and Brn3a downstream targets, including TrkA and Bcl-xL. (B) In control (wild type) trigeminal ganglion, programmed cell death can be detected from E10.5 to E15.5, and reaches its maximum at E11.5 and E13.5. Due to the opposing effects of Brn3a and HIPK2 in regulating the expression of TrkA and Bcl-xL, loss of Brn3a leads to increase in neuronal apoptosis and expansion of the period of programmed cell death in trigeminal ganglion at E15.5 and E17.5. In contrast, loss of HIPK2 leads to reduced apoptosis at E13.5 and E15.5.
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fig8: Proposed model for Brn3a and HIPK2 in transcriptional control of gene expression in sensory neurons. (A) HIPK2 is a transcriptional corepressor for Brn3a-mediated gene expression. HIPK2 interacts with Brn3a and suppresses Brn3a auto-regulatory activity and Brn3a downstream targets, including TrkA and Bcl-xL. (B) In control (wild type) trigeminal ganglion, programmed cell death can be detected from E10.5 to E15.5, and reaches its maximum at E11.5 and E13.5. Due to the opposing effects of Brn3a and HIPK2 in regulating the expression of TrkA and Bcl-xL, loss of Brn3a leads to increase in neuronal apoptosis and expansion of the period of programmed cell death in trigeminal ganglion at E15.5 and E17.5. In contrast, loss of HIPK2 leads to reduced apoptosis at E13.5 and E15.5.

Mentions: Maintenance of neuronal survival depends on a balanced expression of prosurvival and proapoptotic genes. Results from this work demonstrate that transcriptional corepressor HIPK2 negatively regulates Brn3a-mediated neuronal survival in the developing sensory ganglia. The mechanism by which HIPK2 regulates Brn3a is mediated through protein–protein interaction, which suppresses the Brn3a-dependent transcription of brn3a, trkA, and bcl-xL loci. As a consequence, overexpression of HIPK2 mimics the phenotype of the Brn3a−/− mutants, resulting in apoptotic cell death in cultured sensory neurons. Conversely, loss of HIPK2 leads to a stage-specific up-regulation of Brn3a and Brn3a target genes, reduced apoptosis, and increased neuron number in the trigeminal ganglion in vivo. Together, these data support the model that interaction between Brn3a and HIPK2 regulates gene expression, apoptosis, and neuronal survival during trigeminal ganglion development (Fig. 8 A). Due to their important roles in regulating the expression of TrkA and Bcl-xL, loss of Brn3a or HIPK2 leads, respectively, to either increased or reduced programmed cell death (Fig. 8 B).


Interaction of Brn3a and HIPK2 mediates transcriptional repression of sensory neuron survival.

Wiggins AK, Wei G, Doxakis E, Wong C, Tang AA, Zang K, Luo EJ, Neve RL, Reichardt LF, Huang EJ - J. Cell Biol. (2004)

Proposed model for Brn3a and HIPK2 in transcriptional control of gene expression in sensory neurons. (A) HIPK2 is a transcriptional corepressor for Brn3a-mediated gene expression. HIPK2 interacts with Brn3a and suppresses Brn3a auto-regulatory activity and Brn3a downstream targets, including TrkA and Bcl-xL. (B) In control (wild type) trigeminal ganglion, programmed cell death can be detected from E10.5 to E15.5, and reaches its maximum at E11.5 and E13.5. Due to the opposing effects of Brn3a and HIPK2 in regulating the expression of TrkA and Bcl-xL, loss of Brn3a leads to increase in neuronal apoptosis and expansion of the period of programmed cell death in trigeminal ganglion at E15.5 and E17.5. In contrast, loss of HIPK2 leads to reduced apoptosis at E13.5 and E15.5.
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fig8: Proposed model for Brn3a and HIPK2 in transcriptional control of gene expression in sensory neurons. (A) HIPK2 is a transcriptional corepressor for Brn3a-mediated gene expression. HIPK2 interacts with Brn3a and suppresses Brn3a auto-regulatory activity and Brn3a downstream targets, including TrkA and Bcl-xL. (B) In control (wild type) trigeminal ganglion, programmed cell death can be detected from E10.5 to E15.5, and reaches its maximum at E11.5 and E13.5. Due to the opposing effects of Brn3a and HIPK2 in regulating the expression of TrkA and Bcl-xL, loss of Brn3a leads to increase in neuronal apoptosis and expansion of the period of programmed cell death in trigeminal ganglion at E15.5 and E17.5. In contrast, loss of HIPK2 leads to reduced apoptosis at E13.5 and E15.5.
Mentions: Maintenance of neuronal survival depends on a balanced expression of prosurvival and proapoptotic genes. Results from this work demonstrate that transcriptional corepressor HIPK2 negatively regulates Brn3a-mediated neuronal survival in the developing sensory ganglia. The mechanism by which HIPK2 regulates Brn3a is mediated through protein–protein interaction, which suppresses the Brn3a-dependent transcription of brn3a, trkA, and bcl-xL loci. As a consequence, overexpression of HIPK2 mimics the phenotype of the Brn3a−/− mutants, resulting in apoptotic cell death in cultured sensory neurons. Conversely, loss of HIPK2 leads to a stage-specific up-regulation of Brn3a and Brn3a target genes, reduced apoptosis, and increased neuron number in the trigeminal ganglion in vivo. Together, these data support the model that interaction between Brn3a and HIPK2 regulates gene expression, apoptosis, and neuronal survival during trigeminal ganglion development (Fig. 8 A). Due to their important roles in regulating the expression of TrkA and Bcl-xL, loss of Brn3a or HIPK2 leads, respectively, to either increased or reduced programmed cell death (Fig. 8 B).

Bottom Line: Overexpression of HIPK2 induces apoptosis in cultured sensory neurons.Conversely, targeted deletion of HIPK2 leads to increased expression of Brn3a, TrkA, and Bcl-xL, reduced apoptosis and increases in neuron numbers in the trigeminal ganglion.Together, these data indicate that HIPK2, through regulation of Brn3a-dependent gene expression, is a critical component in the transcriptional machinery that controls sensory neuron survival.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, University of California San Francisco, San Francisco, CA 94143, USA.

ABSTRACT
The Pit1-Oct1-Unc86 domain (POU domain) transcription factor Brn3a controls sensory neuron survival by regulating the expression of Trk receptors and members of the Bcl-2 family. Loss of Brn3a leads to a dramatic increase in apoptosis and severe loss of neurons in sensory ganglia. Although recent evidence suggests that Brn3a-mediated transcription can be modified by additional cofactors, the exact mechanisms are not known. Here, we report that homeodomain interacting protein kinase 2 (HIPK2) is a pro-apoptotic transcriptional cofactor that suppresses Brn3a-mediated gene expression. HIPK2 interacts with Brn3a, promotes Brn3a binding to DNA, but suppresses Brn3a-dependent transcription of brn3a, trkA, and bcl-xL. Overexpression of HIPK2 induces apoptosis in cultured sensory neurons. Conversely, targeted deletion of HIPK2 leads to increased expression of Brn3a, TrkA, and Bcl-xL, reduced apoptosis and increases in neuron numbers in the trigeminal ganglion. Together, these data indicate that HIPK2, through regulation of Brn3a-dependent gene expression, is a critical component in the transcriptional machinery that controls sensory neuron survival.

Show MeSH
Related in: MedlinePlus