| First Author | Shang Y | Year | 2018 |
| Journal | J Neurosci | Volume | 38 |
| Issue | 16 | Pages | 4006-4019 |
| PubMed ID | 29581378 | Mgi Jnum | J:261797 |
| Mgi Id | MGI:6154521 | Doi | 10.1523/JNEUROSCI.3577-17.2018 |
| Citation | Shang Y, et al. (2018) HIPK2-Mediated Transcriptional Control of NMDA Receptor Subunit Expression Regulates Neuronal Survival and Cell Death. J Neurosci 38(16):4006-4019 |
| abstractText | NMDA receptors are critical for neuronal communication. Dysfunction in NMDA receptors has been implicated in neuropsychiatric diseases. While it is well recognized that the composition of NMDA receptors undergoes a GluN2B-to-GluN2A switch in early postnatal life, the mechanism regulating this switch remains unclear. Using transcriptomic and functional analyses in brain tissues from male and female Hipk2(+/+) and Hipk2(-/-) mice, we showed that the HIPK2-JNK-c-Jun pathway is important in suppressing the transcription of Grin2a and Grin2c, which encodes the GluN2A and GluN2C subunits of the NMDA receptors, respectively. Loss of HIPK2 leads to a significant decrease in JNK-c-Jun signaling, which in turn derepresses the transcription of Grin2a and Grin2c mRNA and upregulates GluN2A and GluN2C protein levels. These changes result in a significant increase of GluN2A/GluN2B ratio in synapse and mitochondria, a persistent activation of the ERK-CREB pathway and the upregulation of synaptic activity-regulated genes, which collectively contribute to the resistance of Hipk2(-/-) neurons to cell death induced by mitochondrial toxins.SIGNIFICANCE STATEMENT We identify HIPK2-JNK-c-Jun signaling as a key mechanism that regulates the transcription of NMDA receptor subunits GluN2A and GluN2C in vivo Our results provide insights into a previously unrecognized molecular mechanism that control the switch of NMDA receptor subunits in early postnatal brain development. Furthermore, we provide evidence that changes in the ratio of NMDA subunits GluN2A/GluN2B can also be detected in the synapse and mitochondria, which contributes to a persistent activation of the prosurvival ERK-CREB pathway and its downstream target genes. Collectively, these changes protect HIPK2 deficient neurons from mitochondrial toxins. |
