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Involvement of PLAGL1/ZAC1 in hypocretin/orexin transcription.

ABSTRACT: The hypocretin/orexin neuropeptide system coordinates the regulation of various physiological processes. Our previous study reported that a reduction in the expression of pleomorphic adenoma gene?like 1 (Plagl1), which encodes a C2H2 zinc?finger transcription factor, occurs in hypocretin neuron?ablated transgenic mice, suggesting that PLAGL1 is co?expressed in hypocretin neurons and regulates hypocretin transcription. The present study examined whether canonical prepro?hypocretin transcription is functionally modulated by PLAGL1. Double immunostaining indicated that the majority of hypocretin neurons were positive for PLAGL1 immunoreactivity in the nucleus. Notably, PLAGL1 immunoreactivity in hypocretin neurons was altered in response to several conditions affecting hypocretin function. An uneven localization of PLAGL1 was detected in the nuclei of hypocretin neurons following sleep deprivation. Chromatin immunoprecipitation revealed that endogenous PLAGL1 may bind to a putative PLAGL1?binding site in the proximal region of the hypocretin gene, in the murine hypothalamus. In addition, electroporation of the PLAGL1 expression vector into the fetal hypothalamus promoted hypothalamic hypocretin transcription. These results suggested that PLAGL1 may regulate hypothalamic hypocretin transcription.

SUBMITTER: Tanaka S

PROVIDER: S-EPMC6445593 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Involvement of PLAGL1/ZAC1 in hypocretin/orexin transcription.

Tanaka Susumu S Honda Yoshiko Y Takaku Shizuka S Koike Taro T Oe Souichi S Hirahara Yukie Y Yoshida Takashi T Takizawa Nae N Takamori Yasuharu Y Kurokawa Kiyoshi K Kodama Tohru T Yamada Hisao H

International journal of molecular medicine 20190320 5

The hypocretin/orexin neuropeptide system coordinates the regulation of various physiological processes. Our previous study reported that a reduction in the expression of pleomorphic adenoma gene‑like 1 (Plagl1), which encodes a C2H2 zinc‑finger transcription factor, occurs in hypocretin neuron‑ablated transgenic mice, suggesting that PLAGL1 is co‑expressed in hypocretin neurons and regulates hypocretin transcription. The present study examined whether canonical prepro‑hypocretin transcription i ...[more]

PMID: 30896835

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Project description:The sleep disorder narcolepsy is caused by a vast reduction in neurons producing the hypocretin (orexin) neuropeptides. Based on the tight association with HLA, narcolepsy is believed to result from an autoimmune attack, but the cause of hypocretin cell loss is still unknown. We performed gene expression profiling in the hypothalamus to identify novel genes dysregulated in narcolepsy, as these may be the target of autoimmune attack or modulate hypocretin gene expression.We used microarrays to compare the transcriptome in the posterior hypothalamus of (1) narcoleptic versus control postmortem human brains and (2) transgenic mice lacking hypocretin neurons versus wild type mice. Hypocretin was the most downregulated gene in human narcolepsy brains. Among many additional candidates, only one, insulin-like growth factor binding protein 3 (IGFBP3), was downregulated in both human and mouse models and co-expressed in hypocretin neurons. Functional analysis indicated decreased hypocretin messenger RNA and peptide content, and increased sleep in transgenic mice overexpressing human IGFBP3, an effect possibly mediated through decreased hypocretin promotor activity in the presence of excessive IGFBP3. Although we found no IGFBP3 autoantibodies nor a genetic association with IGFBP3 polymorphisms in human narcolepsy, we found that an IGFBP3 polymorphism known to increase serum IGFBP3 levels was associated with lower CSF hypocretin-1 in normal individuals.Comparison of the transcriptome in narcolepsy and narcolepsy model mouse brains revealed a novel dysregulated gene which colocalized in hypocretin cells. Functional analysis indicated that the identified IGFBP3 is a new regulator of hypocretin cell physiology that may be involved not only in the pathophysiology of narcolepsy, but also in the regulation of sleep in normal individuals, most notably during adolescence. Further studies are required to address the hypothesis that excessive IGFBP3 expression may initiate hypocretin cell death and cause narcolepsy.

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Involvement of PLAGL1/ZAC1 in hypocretin/orexin transcription.

Publications

Involvement of PLAGL1/ZAC1 in hypocretin/orexin transcription.

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