Limits...
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.

Show MeSH

Related in: MedlinePlus

Expression of HIPK2 in the developing sensory nervous system. (A) HIPK2 mRNA is present in the sensory ganglia, including trigeminal ganglion (TG), vestibulocochlear ganglion (VCG), nodose-petrosal ganglion (NP), and the dorsal root ganglia (DRG) at E12.5. Li, liver. (B–G) Antibodies detect Brn3a and HIPK2 proteins in the DRG (B–D, and F) and TG (E and G) at E12.5. The staining intensity of HIPK2 appears to vary among neurons at E12.5 with a few showing more intense HIPK2 staining (F and G, arrows). Bars: (A) 500 μm; (B and C) 200 μm; (D–G) 50 μm.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2172556&req=5

fig4: Expression of HIPK2 in the developing sensory nervous system. (A) HIPK2 mRNA is present in the sensory ganglia, including trigeminal ganglion (TG), vestibulocochlear ganglion (VCG), nodose-petrosal ganglion (NP), and the dorsal root ganglia (DRG) at E12.5. Li, liver. (B–G) Antibodies detect Brn3a and HIPK2 proteins in the DRG (B–D, and F) and TG (E and G) at E12.5. The staining intensity of HIPK2 appears to vary among neurons at E12.5 with a few showing more intense HIPK2 staining (F and G, arrows). Bars: (A) 500 μm; (B and C) 200 μm; (D–G) 50 μm.

Mentions: To begin to understand the in vivo function of HIPK2, especially in the context of sensory neuron survival during development, we investigated the expression pattern of HIPK2. In situ hybridization using an RNA probe derived from the 39 UTR indicated that HIPK2 mRNA was present in the developing sensory ganglia, including the trigeminal, vestibulocochlear, nodose-petrosal, and dorsal root ganglia (Fig. 4 A). HIPK2 mRNA was also detected in mid-brain/hindbrain regions and in nonneural tissues, such as liver, heart, and kidney (Fig. 4 A and not depicted). Using an antibody that recognized the COOH terminus of HIPK2, HIPK2 was detected in the developing trigeminal and dorsal root ganglia at E12.5 (Fig. 4, C, F, and G). In contrast to the more restricted expression of Brn3a, HIPK2 protein was also detected in the developing spinal cord (Fig. 4, B and C). Interestingly, whereas Brn3a was confined to the nuclei, the distribution of HIPK2 appeared to be more heterogeneous. At E12.5, some neurons showed dense nuclear staining, whereas the staining in others was more diffuse (Fig. 4, F and G, arrows). The presence of HIPK2 protein in the neuronal cytoplasm appeared to be more distinct at postnatal stages, suggesting that the subcellular localization of HIPK2 may change at different stages of neuronal development (not depicted).


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)

Expression of HIPK2 in the developing sensory nervous system. (A) HIPK2 mRNA is present in the sensory ganglia, including trigeminal ganglion (TG), vestibulocochlear ganglion (VCG), nodose-petrosal ganglion (NP), and the dorsal root ganglia (DRG) at E12.5. Li, liver. (B–G) Antibodies detect Brn3a and HIPK2 proteins in the DRG (B–D, and F) and TG (E and G) at E12.5. The staining intensity of HIPK2 appears to vary among neurons at E12.5 with a few showing more intense HIPK2 staining (F and G, arrows). Bars: (A) 500 μm; (B and C) 200 μm; (D–G) 50 μm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2172556&req=5

fig4: Expression of HIPK2 in the developing sensory nervous system. (A) HIPK2 mRNA is present in the sensory ganglia, including trigeminal ganglion (TG), vestibulocochlear ganglion (VCG), nodose-petrosal ganglion (NP), and the dorsal root ganglia (DRG) at E12.5. Li, liver. (B–G) Antibodies detect Brn3a and HIPK2 proteins in the DRG (B–D, and F) and TG (E and G) at E12.5. The staining intensity of HIPK2 appears to vary among neurons at E12.5 with a few showing more intense HIPK2 staining (F and G, arrows). Bars: (A) 500 μm; (B and C) 200 μm; (D–G) 50 μm.
Mentions: To begin to understand the in vivo function of HIPK2, especially in the context of sensory neuron survival during development, we investigated the expression pattern of HIPK2. In situ hybridization using an RNA probe derived from the 39 UTR indicated that HIPK2 mRNA was present in the developing sensory ganglia, including the trigeminal, vestibulocochlear, nodose-petrosal, and dorsal root ganglia (Fig. 4 A). HIPK2 mRNA was also detected in mid-brain/hindbrain regions and in nonneural tissues, such as liver, heart, and kidney (Fig. 4 A and not depicted). Using an antibody that recognized the COOH terminus of HIPK2, HIPK2 was detected in the developing trigeminal and dorsal root ganglia at E12.5 (Fig. 4, C, F, and G). In contrast to the more restricted expression of Brn3a, HIPK2 protein was also detected in the developing spinal cord (Fig. 4, B and C). Interestingly, whereas Brn3a was confined to the nuclei, the distribution of HIPK2 appeared to be more heterogeneous. At E12.5, some neurons showed dense nuclear staining, whereas the staining in others was more diffuse (Fig. 4, F and G, arrows). The presence of HIPK2 protein in the neuronal cytoplasm appeared to be more distinct at postnatal stages, suggesting that the subcellular localization of HIPK2 may change at different stages of neuronal development (not depicted).

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