RESUMEN
Old animals display significant alterations in sleep-wake patterns such as increases in sleep fragmentation and sleep propensity. Here, we demonstrated that PR-domain containing protein 13 (Prdm13)+ neurons in the dorsomedial hypothalamus (DMH) are activated during sleep deprivation (SD) in young mice but not in old mice. Chemogenetic inhibition of Prdm13+ neurons in the DMH in young mice promotes increase in sleep attempts during SD, suggesting its involvement in sleep control. Furthermore, DMH-specific Prdm13-knockout (DMH-Prdm13-KO) mice recapitulated age-associated sleep alterations such as sleep fragmentation and increased sleep attempts during SD. These phenotypes were further exacerbated during aging, with increased adiposity and decreased physical activity, resulting in shortened lifespan. Dietary restriction (DR), a well-known anti-aging intervention in diverse organisms, ameliorated age-associated sleep fragmentation and increased sleep attempts during SD, whereas these effects of DR were abrogated in DMH-Prdm13-KO mice. Moreover, overexpression of Prdm13 in the DMH ameliorated increased sleep attempts during SD in old mice. Therefore, maintaining Prdm13 signaling in the DMH might play an important role to control sleep-wake patterns during aging.
Asunto(s)
Hipotálamo , Privación de Sueño , Ratones , Animales , Hipotálamo/metabolismo , Privación de Sueño/metabolismo , Obesidad/metabolismo , Sueño , Dieta , N-Metiltransferasa de Histona-Lisina/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
In general, catechins contained in green tea are believed to have positive effects on the human body and mental health. The intake of epigallocatechin gallate (EGCG), a major polyphenol in green tea, is known to be effective for retinal protection; however, whether green tea and/or EGCG affect visual function remains unknown. In the present study, we investigated the effect of green tea and EGCG on visual motion processing by measuring optokinetic responses (OKRs) in young adult and aging mice. Young and aging mice (C57BL6/J) were fed a control diet (control) or the test diet, which contained matcha green tea powder or green tea extract (dried sencha green tea infusion), for 1 month, and their OKRs were measured. They were then intraperitoneally administered saline (control) or EGCG, and OKRs were measured. We found that the OKRs of young and aging mice after green tea intake and after EGCG administration showed higher temporal sensitivity than those of control mice. The visual ability to detect moving objects was enhanced in young and aging mice upon intake of green tea or EGCG. From the above results, the visual motion processing for optokinetic responses by ingesting green tea was enhanced, which may be related to the effect of EGCG.
Asunto(s)
Catequina , Té , Animales , Antioxidantes , Catequina/análogos & derivados , Catequina/farmacología , Humanos , Ratones , Extractos Vegetales/farmacología , Polifenoles , PolvosRESUMEN
The positive regulatory (PR) domain containing 13 (PRDM13) putative chromatin modifier and transcriptional regulator functions downstream of the transcription factor PTF1A, which controls GABAergic fate in the spinal cord and neurogenesis in the hypothalamus. Here, we report a recessive syndrome associated with PRDM13 mutation. Patients exhibited intellectual disability, ataxia with cerebellar hypoplasia, scoliosis, and delayed puberty with congenital hypogonadotropic hypogonadism (CHH). Expression studies revealed Prdm13/PRDM13 transcripts in the developing hypothalamus and cerebellum in mouse and human. An analysis of hypothalamus and cerebellum development in mice homozygous for a Prdm13 mutant allele revealed a significant reduction in the number of Kisspeptin (Kiss1) neurons in the hypothalamus and PAX2+ progenitors emerging from the cerebellar ventricular zone. The latter was accompanied by ectopic expression of the glutamatergic lineage marker TLX3. Prdm13-deficient mice displayed cerebellar hypoplasia and normal gonadal structure, but delayed pubertal onset. Together, these findings identify PRDM13 as a critical regulator of GABAergic cell fate in the cerebellum and of hypothalamic kisspeptin neuron development, providing a mechanistic explanation for the cooccurrence of CHH and cerebellar hypoplasia in this syndrome. To our knowledge, this is the first evidence linking disrupted PRDM13-mediated regulation of Kiss1 neurons to CHH in humans.
Asunto(s)
Cerebelo/anomalías , N-Metiltransferasa de Histona-Lisina , Hipogonadismo , Hipotálamo/enzimología , Mutación , Malformaciones del Sistema Nervioso , Factores de Transcripción , Animales , Cerebelo/enzimología , Discapacidades del Desarrollo/enzimología , Discapacidades del Desarrollo/genética , Modelos Animales de Enfermedad , N-Metiltransferasa de Histona-Lisina/genética , N-Metiltransferasa de Histona-Lisina/metabolismo , Humanos , Hipogonadismo/enzimología , Hipogonadismo/genética , Ratones , Ratones Mutantes , Malformaciones del Sistema Nervioso/enzimología , Malformaciones del Sistema Nervioso/genética , Neuronas/enzimología , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
BACKGROUND & AIMS: Gastric chief cells, a mature cell type that secretes digestive enzymes, have been proposed to be the origin of metaplasia and cancer through dedifferentiation or transdifferentiation. However, studies supporting this claim have had technical limitations, including issues with the specificity of chief cell markers and the toxicity of drugs used. We therefore sought to identify genes expressed specifically in chief cells and establish a model to trace these cells. METHODS: We performed transcriptome analysis of Mist1-CreERT-traced cells, with or without chief cell depletion. Gpr30-rtTA mice were generated and crossed to TetO-Cre mice, and lineage tracing was performed after crosses to R26-TdTomato mice. Additional lineage tracing experiments were performed using Mist1-CreERT, Kitl-CreERT, Tff1-Cre, and Tff2-Cre mice crossed to reporter mice. Mice were given high-dose tamoxifen or DMP-777 or were infected with Helicobacter pylori to induce gastric metaplasia. We studied mice that expressed mutant forms of Ras in gastric cells, using TetO-KrasG12D, LSL-KrasG12D, and LSL-HrasG12V mice. We analyzed stomach tissues from GPR30-knockout mice. Mice were given dichloroacetate to inhibit pyruvate dehydrogenase kinase (PDK)-dependent cell competition. RESULTS: We identified GPR30, the G-protein-coupled form of the estrogen receptor, as a cell-specific marker of chief cells in gastric epithelium of mice. Gpr30-rtTA mice crossed to TetO-Cre;R26-TdTomato mice had specific expression of GPR30 in chief cells, with no expression noted in isthmus stem cells or lineage tracing of glands. Expression of mutant Kras in GPR30+ chief cells did not lead to the development of metaplasia or dysplasia but, instead, led to a reduction in labeled numbers of chief cells and a compensatory expansion of neck lineage, which was derived from upper Kitl+ clones. Administration of high-dose tamoxifen, DMP-777, or H pylori decreased the number of labeled chief cells. Chief cells were eliminated from epithelia via GPR30- and PDK-dependent cell competition after metaplastic stimuli, whereas loss of GRP30 or inhibition of PDK activity preserved chief cell numbers and attenuated neck lineage cell expansion. CONCLUSIONS: In tracing studies of mice, we found that most chief cells are lost during metaplasia and therefore are unlikely to contribute to gastric carcinogenesis. Expansion of cells that coexpress neck and chief lineage markers, known as spasmolytic polypeptide-expressing metaplasia, does not occur via dedifferentiation from chief cells but, rather, through a compensatory response from neck progenitors to replace the eliminated chief cells.
Asunto(s)
Células Principales Gástricas/fisiología , Mucosa Gástrica/patología , Infecciones por Helicobacter/patología , Helicobacter pylori/patogenicidad , Receptores de Estrógenos/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Animales , Azetidinas/toxicidad , Comunicación Celular/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Linaje de la Célula/efectos de los fármacos , Linaje de la Célula/fisiología , Ácido Dicloroacético/administración & dosificación , Modelos Animales de Enfermedad , Mucosa Gástrica/citología , Mucosa Gástrica/efectos de los fármacos , Infecciones por Helicobacter/microbiología , Humanos , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Metaplasia/inducido químicamente , Metaplasia/microbiología , Metaplasia/patología , Ratones , Ratones Noqueados , Piperazinas/toxicidad , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora/antagonistas & inhibidores , Receptores de Estrógenos/genética , Receptores Acoplados a Proteínas G/genética , Células Madre/fisiología , Tamoxifeno/toxicidadRESUMEN
Primary cilia are sensory organelles that harbor various receptors such as G protein-coupled receptors (GPCRs). We analyzed subcellular localization of 138 non-odorant GPCRs. We transfected GPCR expression vectors into NIH3T3 cells, induced ciliogenesis by serum starvation, and observed subcellular localization of GPCRs by immunofluorescent staining. We found that several GPCRs whose ligands are involved in feeding behavior, including prolactin-releasing hormone receptor (PRLHR), neuropeptide FF receptor 1 (NPFFR1), and neuromedin U receptor 1 (NMUR1), localized to the primary cilia. In addition, we found that a short form of dopamine receptor D2 (DRD2S) is efficiently transported to the primary cilia, while a long form of dopamine receptor D2 (DRD2L) is rarely transported to the primary cilia. Using an anti-Prlhr antibody, we found that Prlhr localized to the cilia on the surface of the third ventricle in the vicinity of the hypothalamic periventricular nucleus. We generated the Npy2r-Cre transgenic mouse line in which Cre-recombinase is expressed under the control of the promoter of Npy2r encoding a ciliary GPCR. By mating Npy2r-Cre mice with Ift80 flox mice, we generated Ift80 conditional knockout (CKO) mice in which Npy2r-positive cilia were diminished in number. We found that Ift80 CKO mice exhibited a body weight increase. Our results suggest that Npy2r-positive cilia are important for body weight control.