Molecular mechanisms regulating animal seasonal breeding in response to changing photoperiod are not well understood. Rapid induction of gene expression of thyroid-hormone-activating enzyme (type 2 deiodinase, DIO2) in the mediobasal hypothalamus (MBH) of the Japanese quail (Coturnix japonica) is the earliest event yet recorded in the photoperiodic signal transduction pathway. Here we show cascades of gene expression in the quail MBH associated with the initiation of photoinduced secretion of luteinizing hormone. We identified two waves of gene expression. The first was initiated about 14 h after dawn of the first long day and included increased thyrotrophin (TSH) beta-subunit expression in the pars tuberalis; the second occurred approximately 4 h later and included increased expression of DIO2. Intracerebroventricular (ICV) administration of TSH to short-day quail stimulated gonadal growth and expression of DIO2 which was shown to be mediated through a TSH receptor-cyclic AMP (cAMP) signalling pathway. Increased TSH in the pars tuberalis therefore seems to trigger long-day photoinduced seasonal breeding.
Schnurri-2 (Shn-2), an nuclear factor-κB site-binding protein, tightly binds to the enhancers of major histocompatibility complex class I genes and inflammatory cytokines, which have been shown to harbor common variant single-nucleotide polymorphisms associated with schizophrenia. Although genes related to immunity are implicated in schizophrenia, there has been no study showing that their mutation or knockout (KO) results in schizophrenia. Here, we show that Shn-2 KO mice have behavioral abnormalities that resemble those of schizophrenics. The mutant brain demonstrated multiple schizophrenia-related phenotypes, including transcriptome/proteome changes similar to those of postmortem schizophrenia patients, decreased parvalbumin and GAD67 levels, increased theta power on electroencephalograms, and a thinner cortex. Dentate gyrus granule cells failed to mature in mutants, a previously proposed endophenotype of schizophrenia. Shn-2 KO mice also exhibited mild chronic inflammation of the brain, as evidenced by increased inflammation markers (including GFAP and NADH/NADPH oxidase p22 phox), and genome-wide gene expression patterns similar to various inflammatory conditions. Chronic administration of anti-inflammatory drugs reduced hippocampal GFAP expression, and reversed deficits in working memory and nest-building behaviors in Shn-2 KO mice. These results suggest that genetically induced changes in immune system can be a predisposing factor in schizophrenia.
Using the method of gene targeting in mouse embryonic stem cells, regulatory function of δEF1, a zinc finger and homeodomain-containing transcription factor, was investigated in vivo by generating the δEF1 mutant mice. The mutated allele of δEF1 produced a truncated form of the δEF1 protein lacking a zinc finger cluster proximal to COOH terminus. The homozygous δEF1 mutant mice had poorly developed thymi with no distinction of cortex and medulla. Analysis of the mutant thymocyte showed reduction of the total cell number by two orders of magnitude accompanying the impaired thymocyte development. The early stage intrathymic c-kit+ T precursor cells were largely depleted. The following thymocyte development also seemed to be affected as assessed by the distorted composition of CD4- or CD8-expressing cells. The mutant thymocyte showed elevated α4 integrin expression, which might be related to the T cell defect in the mutant mice. In the peripheral lymph node tissue of the mutant mice, the CD4−CD8+ single positive cells were significantly reduced relative to CD4+CD8− single positive cells. In contrast to T cells, other hematopoietic lineages appeared to be normal. The data indicated that δEF1 is involved in regulation of T cell development at multiple stages.
Adipocyte differentiation is an important component of obesity, but how hormonal cues mediate adipocyte differentiation remains elusive. BMP stimulates in vitro adipocyte differentiation, but the role of BMP in adipogenesis in vivo is unknown. Drosophila Schnurri (Shn) is required for the signaling of Decapentaplegic, a Drosophila BMP homolog, via interaction with the Mad/Medea transcription factors. Vertebrates have three Shn orthologs, Shn-1, -2, and -3. Here, we report that Shn-2(-/-) mice have reduced white adipose tissue and that Shn-2(-/-) mouse embryonic fibroblasts cannot efficiently differentiate into adipocytes in vitro. Shn-2 enters the nucleus upon BMP-2 stimulation and, in cooperation with Smad1/4 and C/EBPalpha, induces the expression of PPARgamma2, a key transcription factor for adipocyte differentiation. Shn-2 directly interacts with both Smad1/4 and C/EBPalpha on the PPARgamma2 promoter. These results indicate that Shn-2-mediated BMP signaling has a critical role in adipogenesis.
Expression of Oct3/4, Sox2, Klf4, and c-Myc (OSKM) can reprogram somatic cells into induced pluripotent stem cells (iPSCs). Somatic cell nuclear transfer (SCNT) can also be used for reprogramming, suggesting that factors present in oocytes could potentially augment OSKM-mediated induction of pluripotency. Here, we report that two histone variants, TH2A and TH2B, which are highly expressed in oocytes and contribute to activation of the paternal genome after fertilization, enhance OSKM-dependent generation of iPSCs and can induce reprogramming with Klf4 and Oct3/4 alone. TH2A and TH2B are enriched on the X chromosome during the reprogramming process, and their expression in somatic cells increases the DNase I sensitivity of chromatin. In addition, Xist deficiency, which was reported to enhance SCNT reprogramming efficiency, stimulates iPSC generation using TH2A/TH2B in conjunction with OSKM, but not OSKM alone. Thus, TH2A/TH2B may enhance reprogramming by introducing processes that normally operate in zygotes and during SCNT.
The molecular mechanisms underlying photoperiodic time measurement are not well understood in any organism. Relatively recently, however, it has become clear that thyroid hormones play an important role in photoperiodism, and in a previous study we reported that long daylengths in Japanese quail increase hypothalamic levels of T(3) and of the thyroid hormone-activating enzyme, type 2 iodothyronine deiodinase. The present study extends these observations to measure gene levels of the thyroid hormone-inactivating enzyme, type 3 deiodinase. Levels decreased after exposure to long days, but increased under short days. Changes in the two genes were then analyzed during the precisely timed photoinduction that occurs in quail exposed to a single long day. The two gene switches are the earliest events yet recorded in the photoinduction process, and overall, these reciprocal changes offer the potential to regulate active brain thyroid hormone concentrations rather precisely at the site in the brain where photoinduction is triggered.
bTumor necrosis factor alpha (TNF-␣) plays a role in apoptosis and proliferation in multiple types of cells, and defects in TNF-␣-induced apoptosis are associated with various autoimmune diseases. Here, we show that TRIM27, a tripartite motif (TRIM) protein containing RING finger, B-box, and coiled-coil domains, positively regulates TNF-␣-induced apoptosis. Trim27-deficient mice are resistant to TNF-␣-D-galactosamine-induced hepatocyte apoptosis. Trim27-deficient mouse embryonic fibroblasts (MEFs) are also resistant to TNF-␣-cycloheximide-induced apoptosis. TRIM27 forms a complex with and ubiquitinates the ubiquitin-specific protease USP7, which deubiquitinates receptor-interacting protein 1 (RIP1), resulting in the positive regulation of TNF-␣-induced apoptosis. Our findings indicate that the ubiquitination-deubiquitination cascade mediated by the TRIM27-USP7 complex plays an important role in TNF-␣-induced apoptosis.
Many symptoms induced by isolation rearing of rodents may be relevant to neuropsychiatric disorders, including depression. However, identities of transcription factors that regulate gene expression in response to chronic social isolation stress remain elusive. The transcription factor ATF‐7 is structurally related to ATF‐2, which is activated by various stresses, including inflammatory cytokines. Here, we report that Atf‐7‐deficient mice exhibit abnormal behaviours and increased 5‐HT receptor 5B (Htr5b) mRNA levels in the dorsal raphe nuclei. ATF‐7 silences the transcription of Htr5B by directly binding to its 5′‐regulatory region, and mediates histone H3‐K9 trimethylation via interaction with the ESET histone methyltransferase. Isolation‐reared wild‐type (WT) mice exhibit abnormal behaviours that resemble those of Atf‐7‐deficient mice. Upon social isolation stress, ATF‐7 in the dorsal raphe nucleus is phosphorylated via p38 and is released from the Htr5b promoter, leading to the upregulation of Htr5b. Thus, ATF‐7 may have a critical role in gene expression induced by social isolation stress.
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