Pancreatic ␤-cells are critical regulators of glucose homeostasis, and they vary dramatically in their glucose stimulated metabolic response and levels of insulin secretion. It is unclear whether these parameters are influenced by the developmental origin of individual ␤-cells. Using HOTcre, a Cre-based genetic switch that uses heat-induction to precisely control the temporal expression of transgenes, we labeled two populations of ␤-cells within the developing zebrafish pancreas. These populations originate in distinct pancreatic buds and exhibit gene expression profiles suggesting distinct functions during development. We find that the dorsal bud derived ␤-cells are quiescent and exhibit a marked decrease in insulin expression postembryonically. In contrast, ventral bud derived ␤-cells proliferate actively, and maintain high levels of insulin expression compared with dorsal bud derived ␤-cells. Therapeutic strategies to regulate ␤-cell proliferation and function are required to cure pathological states that result from excessive ␤-cell proliferation (e.g., insulinoma) or insufficient ␤-cell mass (e.g., diabetes mellitus). Our data reveal the existence of distinct populations of ␤-cells in vivo and should help develop better strategies to regulate ␤-cell differentiation and proliferation.zebrafish ͉ pancreas ͉ islet ͉ insulin ͉ lineage

Acute liver failure in infancy accompanied by lactic acidemia was previously shown to result from mtDNA depletion. We report on 13 unrelated infants who presented with acute liver failure and lactic acidemia with normal mtDNA content. Four died during the acute episodes, and the survivors never had a recurrence. The longest follow-up period was 14 years. Using homozygosity mapping, we identified mutations in the TRMU gene, which encodes a mitochondria-specific tRNA-modifying enzyme, tRNA 5-methylaminomethyl-2-thiouridylate methyltransferase. Accordingly, the 2-thiouridylation levels of the mitochondrial tRNAs were markedly reduced. Given that sulfur is a TRMU substrate and its availability is limited during the neonatal period, we propose that there is a window of time whereby patients with TRMU mutations are at increased risk of developing liver failure.

At the end of the body text, after ''predominantly when the onset is at 1-4 months of age.'', the following sentences should have been included: ''Another Israeli infant of Yemenite-Jewish origin, who presented with transient liver failure during infancy, was previously reported by Lev et al. 17 In view of the similar presentation and ethnic origin, this patient could represent the first reported case of TRMU deficiency.

By combining exome sequencing in conjunction with genetic mapping, we have identified the first mutation in large mitochondrial ribosomal protein MRPL3 in a family of four sibs with hypertrophic cardiomyopathy, psychomotor retardation, and multiple respiratory chain deficiency. Affected sibs were compound heterozygotes for a missense MRPL3 mutation (P317R) and a large-scale deletion, inherited from the mother and the father, respectively. These mutations were shown to alter ribosome assembly and cause a mitochondrial translation deficiency in cultured skin fibroblasts resulting in an abnormal assembly of several complexes of the respiratory chain. This observation gives support to the view that exome sequencing combined with genetic mapping is a powerful approach for the identification of new genes of mitochondrial disorders.

The adaptive response to extreme endurance exercise might involve transcriptional and translational regulation by microRNAs (miRNAs). Therefore, the objective of the present study was to perform an integrated analysis of the blood transcriptome and miRNome (using microarrays) in the horse before and after a 160 km endurance competition. A total of 2,453 differentially expressed genes and 167 differentially expressed microRNAs were identified when comparing pre-and post-ride samples. We used a hypergeometric test and its generalization to gain a better understanding of the biological functions regulated by the differentially expressed microRNA. In particular, 44 differentially expressed microRNAs putatively regulated a total of 351 depleted differentially expressed genes involved variously in glucose metabolism, fatty acid oxidation, mitochondrion biogenesis, and immune response pathways. In an independent validation set of animals, graphical Gaussian models confirmed that miR-21-5p, miR-181b-5p and miR-505-5p are candidate regulatory molecules for the adaptation to endurance exercise in the horse. To the best of our knowledge, the present study is the first to provide a comprehensive, integrated overview of the microRNA-mRNA co-regulation networks that may have a key role in controlling post-transcriptomic regulation during endurance exercise.The physiological and biochemical demands of endurance exercise elicit both muscle-based and systemic responses. The main adaptations to endurance exercise include improvement of mechanical, metabolic, neuromuscular and contractile functions in muscle 1 , correction of electrolyte imbalance 2 , a decrease in glycogen storage 3 and an increase in mitochondrial biogenesis in muscle tissue 4 , and the modulation of oxidative stress 5 , intestinal permeability, muscle damage, systemic inflammation and immune responses 5 . Consequently, adaptations to endurance exercise are influenced by the transcriptional and translational regulation of genes that encode the proteins controlling these processes 5 . Over the past decade, microRNAs (miRNAs) have emerged as novel elements in the rapid, reversible regulation of transcription and translation 6 . MiRNAs are small non-coding RNAs molecules (~19-24 bp in length) that are synthesized from short hairpin precursors and that reportedly degrade or inhibit the translation of their target genes by binding to the 3′ untranslated region (UTR) of coding mRNAs 7 . In fact, miRNAs molecules may regulate up to one-third of the mammalian transcriptome 8 and appear to be stable outside the cell (e.g. when incorporated into exosomes 9 , microvesicles 10 , lipoproteins 11 or Argonaute2 protein complexes 12 ).

Multiple respiratory chain deficiencies represent a common cause of mitochondrial diseases and are associated with a wide range of clinical symptoms. We report a subject, born to consanguineous parents, with growth retardation and neurological deterioration. Multiple respiratory chain deficiency was found in muscle and fibroblasts of the subject as well as abnormal assembly of complexes I and IV. A microsatellite genotyping of the family members detected only one region of homozygosity on chromosome 17q24.2–q25.3 in which we focused our attention to genes involved in mitochondrial translation. We sequenced MRPL12, encoding the mitochondrial ribosomal protein L12 and identified a c.542C>T transition in exon 5 changing a highly conserved alanine into a valine (p.Ala181Val). This mutation resulted in a decreased steady-state level of MRPL12 protein, with altered integration into the large ribosomal subunit. Moreover, an overall mitochondrial translation defect was observed in the subject's fibroblasts with a significant reduction of synthesis of COXI, COXII and COXIII subunits. Modeling of MRPL12 shows Ala181 positioned in a helix potentially involved in an interface of interaction suggesting that the p.Ala181Val change might be predicted to alter interactions with the elongation factors. These results contrast with the eubacterial orthologues of human MRPL12, where L7/L12 proteins do not appear to have a selective effect on translation. Therefore, analysis of the mutated version found in the subject presented here suggests that the mammalian protein does not function in an entirely analogous manner to the eubacterial L7/L12 equivalent.

No abstract

Multiple respiratory chain deficiencies represent a common cause of mitochondrial diseases and often result in hepatic failure.