The Institute of Physiology of the Czech Academy of Sciences (CAS) has been involved in the field of chronobiology, i.e., in research on temporal regulation of physiological processes, since 1970. The review describes the first 35 years of the research mostly on the effect of light and daylength, i.e., photoperiod, on entrainment or resetting of the pineal rhythm in melatonin production and of intrinsic rhythms in the central biological clock. This clock controls pineal and other circadian rhythms and is located in the suprachiasmatic nuclei (SCN) of the hypothalamus. During the early chronobiological research, many original findings have been reported, e.g. on mechanisms of resetting of the pineal rhythm in melatonin production by short light pulses or by long exposures of animals to light at night, on modulation of the nocturnal melatonin production by the photoperiod or on the presence of high affinity melatonin binding sites in the SCN. The first evidence was given that the photoperiod modulates functional properties of the SCN and hence the SCN not only controls the daily programme of the organism but it may serve also as a calendar measuring the time of a year. During all the years, the chronobiological community has started to talk about "the Czech school of chronobiology". At present, the today´s Laboratory of Biological Rhythms of the Institute of Physiology CAS continues in the chronobiological research and the studies have been extended to the entire circadian timekeeping system in mammals with focus on its ontogenesis, entrainment mechanisms and circadian regulation of physiological functions. Key words: Pineal, Melatonin, AA-NAT rhythm, Light entrainment, Photoperiod, SCN clock.

• MeSH
• akademie a ústavy MeSH
• biologické hodiny fyziologie   MeSH
• cirkadiánní hodiny fyziologie   MeSH
• cirkadiánní rytmus * fyziologie   MeSH
• dějiny 20. století MeSH
• dějiny 21. století MeSH
• epifýza mozková * metabolismus   fyziologie   MeSH
• fotoperioda MeSH
• lidé MeSH
• melatonin metabolismus   MeSH
• mozek metabolismus   fyziologie   MeSH
• nucleus suprachiasmaticus fyziologie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• dějiny 20. století MeSH
• dějiny 21. století MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• historické články MeSH
• přehledy MeSH
• Názvy látek
• melatonin MeSH

Normal neurodevelopment requires precise expression of the key ubiquitin ligase gene Ube3a. Comparing newly generated mouse models for Ube3a downregulation (models of Angelman syndrome) vs. Ube3a upregulation (models for autism), we find reciprocal effects of Ube3a gene dosage on phenotypes associated with circadian rhythmicity, including the amount of locomotor activity. Consistent with results from neurons in general, we find that Ube3a is imprinted in neurons of the suprachiasmatic nuclei (SCN), the pacemaking circadian brain locus, despite other claims that SCN neurons were somehow exceptional to these imprinting rules. In addition, Ube3a-deficient mice lack the typical drop in wake late in the dark period and have blunted responses to sleep deprivation. Suppression of physical activity by light in Ube3a-deficient mice is not due to anxiety as measured by behavioral tests and stress hormones; quantification of stress hormones may provide a mechanistic link to sleep alteration and memory deficits caused by Ube3a deficiency, and serve as an easily measurable biomarker for evaluating potential therapeutic treatments for Angelman syndrome. We conclude that reduced Ube3a gene dosage affects not only neurodevelopment but also sleep patterns and circadian rhythms.

• Klíčová slova
• Angelman syndrome, UBE3A (E6AP), autism, circadian, imprinting, neurodevelopmental disorders, sleep, ubiquitin ligase,
• Publikační typ
• časopisecké články MeSH

Angelman syndrome (AS) is a rare genetic disorder characterized by severe intellectual disability, seizures, lack of speech, and ataxia. The gene responsible for AS was identified as Ube3a and it encodes for E6AP, an E3 ubiquitin ligase. Currently, there is very little known about E6AP's mechanism of action in vivo or how the lack of this protein in neurons may contribute to the AS phenotype. Elucidating the mechanistic action of E6AP would enhance our understanding of AS and drive current research into new avenues that could lead to novel therapeutic approaches that target E6AP's various functions. To facilitate the study of AS, we have generated a novel rat model in which we deleted the rat Ube3a gene using CRISPR. The AS rat phenotypically mirrors human AS with loss of Ube3a expression in the brain and deficits in motor coordination as well as learning and memory. This model offers a new avenue for the study of AS. Autism Res 2020, 13: 397-409. © 2020 International Society for Autism Research,Wiley Periodicals, Inc. LAY SUMMARY: Angelman syndrome (AS) is a rare genetic disorder characterized by severe intellectual disability, seizures, difficulty speaking, and ataxia. The gene responsible for AS was identified as UBE3A, yet very little is known about its function in vivo or how the lack of this protein in neurons may contribute to the AS phenotype. To facilitate the study of AS, we have generated a novel rat model in which we deleted the rat Ube3a gene using CRISPR. The AS rat mirrors human AS with loss of Ube3a expression in the brain and deficits in motor coordination as well as learning and memory. This model offers a new avenue for the study of AS.

• Klíčová slova
• Angelman syndrome, E6AP, Ube3a, cognitive deficits, rat model,
• MeSH
• Angelmanův syndrom genetika   patofyziologie   MeSH
• delece genu * MeSH
• fenotyp MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• mozek patofyziologie   MeSH
• paměť MeSH
• potkani Sprague-Dawley MeSH
• ubikvitinligasy genetika   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• Ube3a protein, rat MeSH Prohlížeč
• ubikvitinligasy MeSH

Rhythmicity of the rat suprachiasmatic nucleus (SCN), a site of the circadian clock, develops prenatally. A molecular clockwork responsible for the rhythmicity consists of clock genes and their negative and positive transcriptional-translational feedback loops. The aim of the present study was to discover the development of the clockwork during ontogenesis. Daily profiles of Per1, Per2, Cry1, Bmal1, and Clock mRNA in the SCN of fetuses at the embryonic day (E)19 and of newborn rats at the postnatal day (P)3 and P10 were assessed by the in situ hybridization method. In addition, daily profiles of PER1, PER2, and CRY1 proteins at E19 were assessed by immunohistochemistry. As early as at E19, all the studied clock genes were already expressed in the SCN. However, no SCN rhythm in their expression was detected; Per1, Cry1, and Clock mRNA levels were low, whereas Bmal1 mRNA levels were high and Per2 mRNA levels were medium. Moreover, no rhythms of PER1, PER2, and CRY1 were detectable, as no immunoreactive cells were present at E19. At P3, rhythms in Per1, Per2, Cry1, and Bmal1, but not in Clock mRNA, were expressed in the SCN. The rhythm matured gradually; at P10, the amplitude of Per1, Per2, and Bmal1 mRNA rhythms was more pronounced than at P3. Altogether, the data show a gradual development of both the positive and negative elements of the molecular clockwork, from no detectable rhythmicity at E19 to highly developed rhythms at P10.

• MeSH
• cirkadiánní rytmus * MeSH
• hybridizace in situ MeSH
• imunohistochemie MeSH
• krysa rodu Rattus MeSH
• messenger RNA genetika   MeSH
• nucleus suprachiasmaticus embryologie   fyziologie   MeSH
• potkani Wistar MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• messenger RNA MeSH