Perfect timing: a Nobel Prize in Physiology or Medicine for circadian clocks

On October 2,2017,the Nobel Prize in Physiology or Medicine was awarded to Jeffrey Hall and Michael Rosbash of Brandeis University,and Michael Young of Rockefeller University,the three circadian biology trailblazers,for unraveling molecular genetic mechanisms of circadian rhythms.The three Nobel laureates completed their prize-winning works largely 20–30 years ago.Yet,this Noble Prize came with perfect timing:on the one hand,it can

Thyroid-stimulating hormone-thyroid hormone signaling contributes to circadian regulation through repressing clock2/npas2 in zebrafish

Thyroid-stimulating hormone(TSH)is important for the thyroid gland,development,growth,and metabolism.Defects in TSH production or the thyrotrope cells within the pituitary gland cause congenital hypothyroidism(CH),resulting in growth retardation and neurocognitive impairment.While human TSH is known to display rhythmicity,the molecular mechanisms underlying the circadian regulation of TSH and the effects of TSH-thyroid hormone(TH)signaling on the circadian clock remain elusive.Here we show that TSH,thyroxine(T4),triiodothyronine(T3),and tshba display rhythmicity in both larval and adult zebrafish and tshba is regulated directly by the circadian clock via both E′-box and D-box.Zebrafish tshba^(−/−)mutants manifest congenital hypothyroidism,with the characteristics of low levels of T_(4)and T_(3)and growth retardation.Loss or overexpression of tshba alters the rhythmicity of locomotor activities and expression of core circadian clock genes and hypothalamic-pituitary-thyroid(HPT)axis-related genes.Furthermore,TSH-TH signaling regulates clock2/npas2 via the thyroid response element(TRE)in its promoter,and transcriptome analysis reveals extensive functions of Tshba in zebrafish.Together,our results demonstrate that zebrafish tshba is a direct target of the circadian clock and in turn plays critical roles in circadian regulation along with other functions.

Zinc finger transcription factor Sp7/Osterix acts on bone formation and regulates col10a1a expression in zebrafish

Sp7/Osterix as a zinc finger transcription factor is expressed specifically in osteoblasts. Embryonic lethality of Sp7 knockout mice, however, has prevented from examining the functions of Sp7 in osteoblast and bone formation in live animals. Here we used TALEN, a versatile genome-editing tool, to generate one zebrafish sp7 mutant line. Homozygous sp7-/- mutant zebrafish are able to survive to adulthood. Alizarin Red staining and Micro-CT analysis showed that sp7-/- larvae and adult fish fail to develop normal opercula, and display curved tail fins and severe craniofacial malformation, while Alcian Blue staining showed no obvious cartilage defects in sp7-/- fish. Quantitative RT-PCR showed that a number of osteoblast markers including sppl, phex, collala, and collalb are significantly down-regulated in sp7-/- fish. Furthermore, col10a1a, whose ortholog is the cartilage marker in mice, was shown to be a novel downstream gene of Sp7 as an osteoblast marker in zebrafish. Together, these results suggest that Sp7 is required for zebrafish bone development and zebrafish sp7 mutants provide animal models for investigating novel aspects of bone development.

Circadian rhythms of melatonin,cortisol,and clock gene expression in the hyperacute phase of wake-up stroke:study design and measurement

To the Editor:Wake-up stroke(WUS)is the name given to an ischemic stroke that occurs primarily during night-time sleep and accounts for approximately 20%of all cases of acute ischemic stroke(AIS).Epidemiological studies have demonstrated a circadian distribution of AIS,with a higher frequency in the morning and a lower frequency during sleep.[1]It remains unclear whether WUS is a stochastic event or if a distinct pathophysiologic process,such as circadian rhythm disorder,differentiates WUS from daytime stroke(non-WUS).

Neuronal and Non-neuronal Cell Types Displaying Circadian Rhythmicity in the Mammalian Suprachiasmatic Nucleus

Circadian rhythms have a period of~24 h and are manifested in almost all living organisms [1].The discovery of the molecular genetic mechanisms underlying circadian rhythmicity was one of the most exciting and inspiring chapters in the history of biology and won the Nobel Prize in Physiology or Medicine in 2017 [2].Equally exciting and inspiring was the discovery that the hypothalamic suprachiasmatic nucleus (SCN) is involved in orchestrating the daily rhythmic activity of physiology。