Abstract-Development of the mammalian heart is governed by precisely orchestrated interactions between signaling pathways integrating environmental cues and a core cardiac transcriptional network that directs differentiation, growth and morphogenesis. Here we report that in mice, at about embryonic day (E)8.5 to E10.0, cardiac development proceeds in an environment that is hypoxic and characterized by high levels of hypoxia-inducible factor (HIF)1␣ protein. Mice lacking HIF1␣ in ventricular cardiomyocytes exhibit aborted development at looping morphogenesis and embryonic lethality between E11.0 to E12.0. Intriguingly, HIF1␣-deficient hearts display reduced expression of the core cardiac transcription factors Mef2C and Tbx5 and of titin, a giant protein that serves as a template for the assembly and organization of the sarcomere. Chromatin immunoprecipitation experiments revealed that Mef2C, Tbx5, and titin are direct target genes of HIF1␣ in vivo. Thus, hypoxia signaling controls cardiac development through HIF1␣-mediated transcriptional regulation of key components of myofibrillogenesis and the cardiac transcription factor network, thereby providing a mechanistic basis of how heart development, morphogenesis, and function is coupled to low oxygen tension during early embryogenesis. Key Words: cardiac development Ⅲ hypoxia Ⅲ transcription Ⅲ myofibrillogenesis Ⅲ HIF1␣ C ardiac development is a multi-stage process governed by a network of transcription factors including Nkx2.5, Tbx5, Mef2C, and GATA4 that connect signaling pathways with the regulation of gene expression for the specification of cardiac cell fate, differentiation and morphogenesis. These transcription factors act in an interconnected and coordinated manner at specific stages of cardiogenesis. Although Nkx2.5 and GATA4 activity is predominantly associated with cardiac lineage specification and differentiation, it is also required for induction of downstream cardiogenic transcription factors such as Tbx5 and Mef2C, whose function is primarily linked to looping morphogenesis and chamber formation. 1 Thus specific transcription factors induce the expression of genes necessary for progression through the respective stages of cardiogenesis. How the expression and activity of these transcription factors are coordinated spatially and temporally in the course of cardiogenesis remains less clear.A central feature of mammalian embryogenesis is the development of intraembryonic hypoxia. 2 As the embryo increases in size, oxygenation of the avascular early postimplantation embryo by diffusion alone becomes limited, leading to a state of regional embryonic hypoxia. In normal development, regional hypoxia has been implicated to serve as a stimulus for the tissue/region-specific induction of genes required for yolk sac vasculogenesis, 3 the establishment of the maternal-fetal circulatory network 4 and the initiation of intraembryonic circulation and cardiac function. 5,6 Thus, the embryonic hypoxic phase is characterized by the coordinated development of multipl...
Homeostatically regulated slow-wave oscillations in non-rapid eye movement (REM) sleep may reflect synaptic changes across the sleep-wake continuum and the restorative function of sleep. The nonsynonymous c.22G>A polymorphism (rs73598374) of adenosine deaminase (ADA) reduces the conversion of adenosine to inosine and predicts baseline differences in sleep slow-wave oscillations. We hypothesized that this polymorphism affects cognitive functions, and investigated whether it modulates electroencephalogram (EEG), behavioral, subjective, and biochemical responses to sleep deprivation. Attention, learning, memory, and executive functioning were quantified in healthy adults. Right-handed carriers of the variant allele (G/A genotype, n = 29) performed worse on the d2 attention task than G/G homozygotes (n = 191). To test whether this difference reflects elevated homeostatic sleep pressure, sleep and sleep EEG before and after sleep deprivation were studied in 2 prospectively matched groups of G/A and G/G genotype subjects. Deep sleep and EEG 0.75- to 1.5-Hz oscillations in non-REM sleep were significantly higher in G/A than in G/G genotype. Moreover, attention and vigor were reduced, whereas waking EEG alpha activity (8.5-12 Hz), sleepiness, fatigue, and α-amylase in saliva were enhanced. These convergent data demonstrate that genetic reduction of ADA activity elevates sleep pressure and plays a key role in sleep and waking quality in humans.
Sleep loss impairs waking functions and is homeostatically compensated in recovery sleep. The mechanisms underlying the consequences of prolonged wakefulness are unknown. The stimulant modafinil may promote primarily dopaminergic neurotransmission. Catechol‐O‐methyltransferase (COMT) catalyzes the breakdown of cerebral dopamine. A functional Val158Met polymorphism reduces COMT activity, and Val/Val homozygous individuals presumably have lower dopaminergic signaling in the prefrontal cortex than do Met/Met homozygotes. We quantified the contribution of this polymorphism to the effects of sleep deprivation and modafinil on subjective state, cognitive performance, and recovery sleep in healthy volunteers. Two‐time 100 mg modafinil potently improved vigor and well‐being, and maintained baseline performance with respect to executive functioning and vigilant attention throughout sleep deprivation in Val/Val genotype subjects but was hardly effective in subjects with the Met/Met genotype. Neither modafinil nor the Val158Met polymorphism affected distinct markers of sleep homeostasis in recovery sleep. In conclusion, dopaminergic mechanisms contribute to impaired waking functions after sleep loss. Clinical Pharmacology & Therapeutics (2009); 85, 3, 296–304 doi:
BDNF contributes to the regulation of sleep slow wave oscillations, suggesting that genetically determined variation in neuronal plasticity modulates NREM sleep intensity in humans.
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