The mammalian circadian system consists of a central oscillator in the suprachiasmatic nucleus of the hypothalamus, which coordinates peripheral clocks in organs throughout the body. Although circadian clocks control the rhythmic expression of a large number of genes involved in metabolism and other aspects of circadian physiology, the consequences of genetic disruption of circadiancontrolled pathways remain poorly defined. Here we report that the targeted disruption of Nocturnin (Ccrn4l) in mice, a gene that encodes a circadian deadenylase, confers resistance to dietinduced obesity. Mice lacking Nocturnin remain lean on high-fat diets, with lower body weight and reduced visceral fat. However, unlike lean lipodystrophic mouse models, these mice do not have fatty livers and do not exhibit increased activity or reduced food intake. Gene expression data suggest that Nocturnin knockout mice have deficits in lipid metabolism or uptake, in addition to changes in glucose and insulin sensitivity. Our data support a pivotal role for Nocturnin downstream of the circadian clockwork in the posttranscriptional regulation of genes necessary for nutrient uptake, metabolism, and storage.C ircadian clocks are present in most tissues of the body, where they control the expression of 5-10% of the tissue-specific mRNAs through both transcriptional and posttranscriptional regulation (1, 2). The widespread importance of circadian clock regulation is evident in that generalized disruption of normal clock function results in tumor formation, sleep disorders, and metabolic problems (reviewed in refs. 3 and 4). For example, mutations in the central clock genes Clock or Bmal1 result in metabolic changes found in obesity and the metabolic syndrome (5-8), and numerous genes involved in fatty acid, cholesterol, and glucose metabolism in liver are regulated in circadian or diurnal patterns (9-15), indicating that the clock plays a broad role in regulating metabolism. Nonetheless, the large number of genes, metabolic pathways, and cell/tissue types that are under general circadian control impose a major challenge in understanding the molecular details. Further advances in this area require refined understanding of the specific circadian output pathways by which the clocks regulate physiology.For cycling mRNAs to closely reflect daily rhythmic transcriptional drive, their half-lives must be relatively short. There are several examples of rhythmic posttranscriptional regulation in which the mRNA half-life or adenylation state changes over the course of the day (16-19), but very little is known about the mechanisms responsible. A likely contributor is Nocturnin (Ccrn4l, Noc), which has been implicated in the posttranscriptional regulation of mRNA stability and/or translatability by the circadian clock (20). Noc is expressed rhythmically in many tissues, with particularly high-amplitude rhythms in liver where mRNA levels are increased 100-fold in early night (21). Noc is at a pivotal position to play a role in shaping the rhythmic pattern of gene ...

The authors have identified a novel null mutation in mouse Mfrp. This mutation causes photoreceptor degeneration and eventual RPE atrophy, which may be related to alterations in the number of RPE microvilli. These mice will be useful to identify a function of MFRP and to study the pathogenesis of atrophic macular degeneration.

We have identified a novel component of the circadian clock that regulates its sensitivity to light at the evening light to dark transition. USP2 (Ubiquitin Specific Protease 2), which de-ubiquitinylates and stabilizes target proteins, is rhythmically expressed in multiple tissues including the SCN. We have developed a knockout model of USP2 and found that exposure to low irradiance light at ZT12 increases phase delays of USP2−/− mice compared to wildtype. We additionally show that USP2b is in a complex with several clock components and regulates the stability and turnover of BMAL1, which in turn alters the expression of several CLOCK/BMAL1 controlled genes. Rhythmic expression of USP2 in the SCN and other tissues offers a new level of control of the clock machinery through de-ubiqutinylation and suggests a role for USP2 during circadian adaptation to environmental day length changes.

Mutations in the gene Centrosomal Protein 290 kDa ( CEP290 ) result in multiple ciliopathies ranging from the neonatal lethal disorder Meckel-Gruber Syndrome to multi-systemic disorders such as Joubert Syndrome and Bardet-Biedl Syndrome to nonsyndromic diseases like Leber Congenital Amaurosis (LCA) and retinitis pigmentosa. Results from model organisms and human genetics studies, have suggest that mutations in genes encoding protein components of the transition zone (TZ) and other cilia-associated proteins can function as genetic modifiers and be a source for CEP290 pleiotropy. We investigated the zebrafish cep290 fh297/fh297 mutant, which encodes a nonsense mutation (p.Q1217*). This mutant is viable as adults, exhibits scoliosis, and undergoes a slow, progressive cone degeneration. The cep290 fh297/fh297 mutants showed partial mislocalization of the transmembrane protein rhodopsin but not of the prenylated proteins rhodopsin kinase (GRK1) or the rod transducin subunit GNB1. Surprisingly, photoreceptor degeneration did not trigger proliferation of Müller glia, but proliferation of rod progenitors in the outer nuclear layer was significantly increased. To determine if heterozygous mutations in other cilia genes could exacerbate retinal degeneration, we bred cep290 fh297/fh297 mutants to arl13b , ahi1 , and cc2d2a mutant zebrafish lines. While cep290 fh297/fh297 mutants lacking a single allele of these genes did not exhibit accelerated photoreceptor degeneration, loss of one alleles of arl13b or ahi1 reduced visual performance in optokinetic response assays at 5 days post fertilization. Our results indicate that the cep290 fh297/fh297 mutant is a useful model to study the role of genetic modifiers on photoreceptor degeneration in zebrafish and to explore how progressive photoreceptor degeneration influences regeneration in adult zebrafish.