The suprachiasmatic nucleus (SCN) is the primary circadian pacemaker in mammals. Individual SCN neurons in dispersed culture can generate independent circadian oscillations of clock gene expression and neuronal firing. However, SCN rhythmicity depends on sufficient membrane depolarization and levels of intracellular calcium and cAMP. In the intact SCN, cellular oscillations are synchronized and reinforced by rhythmic synaptic input from other cells, resulting in a reproducible topographic pattern of distinct phases and amplitudes specified by SCN circuit organization. The SCN network synchronizes its component cellular oscillators, reinforces their oscillations, responds to light input by altering their phase distribution, increases their robustness to genetic perturbations, and enhances their precision. Thus, even though individual SCN neurons can be cell-autonomous circadian oscillators, neuronal network properties are integral to normal function of the SCN.

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Suprachiasmatic Nucleus: Cell Autonomy and Network Properties

Domestic animals are excellent models for genetic studies of phenotypic evolution They have evolved genetic adaptations to a new environment, the farm, and have been subjected to strong human-driven selection leading to remarkable phenotypic changes in morphology, physiology and behaviour Identifying the genetic changes underlying these developments provides new insight into general mechanisms by which genetic variation shapes phenotypic diversity Here we describe the use of massively parallel sequencing to identify selective sweeps of favourable alleles and candidate mutations that have had a prominent role in the domestication of chickens (Gallus gallus domesticus) and their subsequent specialization into broiler (meat-producing) and layer (egg-producing) chickens We have generated 445-fold coverage of the chicken genome using pools of genomic DNA representing eight different populations of domestic chickens as well as red jungle fowl (Gallus gallus), the major wild ancestor We report more than 7,000,000 single nucleotide polymorphisms, almost 1,300 deletions and a number of putative selective sweeps One of the most striking selective sweeps found in all domestic chickens occurred at the locus for thyroid stimulating hormone receptor (TSHR), which has a pivotal role in metabolic regulation and photoperiod control of reproduction in vertebrates Several of the selective sweeps detected in broilers overlapped genes associated with growth, appetite and metabolic regulation We found little evidence that selection for loss-of-function mutations had a prominent role in chicken domestication, but we detected two deletions in coding sequences that we suggest are functionally important This study has direct application to animal breeding and enhances the importance of the domestic chicken as a model organism for biomedical research

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Whole-genome resequencing reveals loci under selection during chicken domestication

The iodothyronine deiodinases initiate or terminate thyroid hormone action and therefore are critical for the biological effects mediated by thyroid hormone. Over the years, research has focused on their role in preserving serum levels of the biologically active molecule T3 during iodine deficiency. More recently, a fascinating new role of these enzymes has been unveiled. The activating deiodinase (D2) and the inactivating deiodinase (D3) can locally increase or decrease thyroid hormone signaling in a tissue- and temporal-specific fashion, independent of changes in thyroid hormone serum concentrations. This mechanism is particularly relevant because deiodinase expression can be modulated by a wide variety of endogenous signaling molecules such as sonic hedgehog, nuclear factor-κB, growth factors, bile acids, hypoxia-inducible factor-1α, as well as a growing number of xenobiotic substances. In light of these findings, it seems clear that deiodinases play a much broader role than once thought, with great ramifications for the control of thyroid hormone signaling during vertebrate development and metamorphosis, as well as injury response, tissue repair, hypothalamic function, and energy homeostasis in adults.

Cellular and Molecular Basis of Deiodinase-Regulated Thyroid Hormone Signaling

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.

Thyrotrophin in the pars tuberalis triggers photoperiodic response

Metals, oxidative stress and neurodegeneration: a focus on iron, manganese and mercury.

Many seasonal breeding animals can estimate the day length (photoperiod) and prepare for breeding in the optimal season. The Japanese quail (Coturnix japonica) is an excellent model for studying photoperiodism because of its rapid and dramatic response to the photoperiod. Recent molecular analysis using the quail has revealed that local thyroid hormone activation by thyroid hormone deiodinases (DIO2 and DIO3) in the mediobasal hypothalamus (MBH) plays a critical role in the regulation of seasonal reproduction in birds. However, the molecular dynamics of gene expression that regulates photoperiodic thyroid hormone activation in the MBH during the photoinduction process remains unclear. The chicken genome project has enabled the analysis of the conservation of the genetic interaction networks for studying photoperiodism. This review focuses on genome-wide transcriptional studies of avian photoperiodism.

Genome-wide Analysis of Seasonal Reproduction in Birds

A new circadian variant was isolated by screening the intercross offspring of wild-caught mice (Mus musculus castaneus). This variant was characterized by an initial maintenance of damped oscillations and subsequent loss of rhythmicity after being transferred from light-dark (LD) cycles to constant darkness (DD). To map the genes responsible for the persistence of rhythmicity (circadian ratio) and the length of free-running period (tau), quantitative trait locus (QTL) analysis was performed using F(2) mice obtained from an F(1) cross between the circadian variant and C57BL/6J mice. As a result, a significant QTL with a main effect for circadian ratio (Arrhythmicity; Arrh-1) was mapped on Chromosome (Chr) 8. For tau, four significant QTLs, Short free-running period (Sfp-1) (Chr 1), Sfp-2 (Chr 6), Sfp-3 (Chr 8), Sfp-4 (Chr 11) were determined. An epistatic interaction was detected between Chr 3 (Arrh-2) and Chr 5 (Arrh-3). An in situ hybridization study of clock genes and mouse Period1::luciferase (mPer1::luc) real-time monitoring analysis in the suprachiasmatic nucleus (SCN) suggested that arrhythmicity in this variant might not be attributed to core circadian mechanisms in the SCN neurons. Our strategy using wild-derived variant mice may provide a novel opportunity to evaluate circadian and its related disorders in human that arise from the interaction between multiple variant genes.

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Genetic and molecular analysis of wild-derived arrhythmic mice.

Imidazole dipeptides (ID) are abundant in skeletal muscle and the brain and have various functions, such as antioxidant, pH-buffering, metal-ion chelation. However, the physiological significance of ID has not been fully elucidated. In this study, we orally administered ID to conventional carnosine synthase gene-deficient mice (Carns-KO mice) to investigate the pharmacokinetics. Carnosine or anserine was administered at a dose of 500 mg (approximately 2 mmol) per kilogram of mouse body weight, and ID contents in the tissues were measured. No ID were detected in untreated Carns-KO mice. In the ID treatment groups, the ID concentrations in the tissues increased in a time-dependent manner in the gastrocnemius muscle, soleus muscle, and cerebrum after ID administration. Our findings suggest that the Carns-KO mice are a valuable animal model for directly evaluate the effects of dietary ID and for elucidating the physiological functions of oral ID administration.

Nobuhiro Nakao

Papers

Genome-wide Analysis of Seasonal Reproduction in Birds

Genetic and molecular analysis of wild-derived arrhythmic mice.

Pharmacokinetics and tissue distribution of orally administrated imidazole dipeptides in carnosine synthase gene knockout mice.