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To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2007.10.026 Byline: Jiandong Liu, Li Qian, Zhe Han, Xiushan Wu, Rolf Bodmer Keywords: Drosophila; Heart; Cardiogenesis; Cell specification; Transcriptional regulation; Epicardium Abstract: Individual cardiac progenitors emerge at defined positions within each segment in the trunk mesoderm. Their specification depends on segmental information from the pre-patterned ectoderm, which provides positional information to the underlying cardiac mesoderm via inductive signals. This pattern is further reinforced by repressive interactions between transcription factors that are expressed in neighboring sets of cardiac progenitors. For example, even-skipped (eve) and ladybird early (lbe) gene products mark adjacent cardiac cell clusters within a segment, and their antagonistic interaction results in mutually exclusive expression domains. Lbe acts directly on the eve mesodermal enhancer (eme) to participate in restricting its expression anteriorly. We hypothesized that additional repressive activities must regulate the precise pattern of eve expression in the cardiac mesoderm via this enhancer. In this study, we identified two additional repressor motifs: 4 copies of an 'AT'-rich motif (M1a-d) and 2 copies of an 'GC'-rich motif (M2a,b), which when mutated cause expansion of eme-dependent reporter gene expression. We have also examined potential negative regulators of eve and found that their overexpression is sufficient to repress eve as well as the eme enhancer via these sites. Our data suggest that a combination of factors is likely to interact with multiple essential repressor sites to confer precise spatial specificity of eve expression in the cardiac mesoderm. Author Affiliation: Development and Aging Program, Center for Neuroscienes, Aging and Stem Cell Research, Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA Article History: Received 10 June 2007; Revised 11 October 2007; Accepted 18 October 2007

Heart development in both vertebrates and Drosophila is initiated by bilaterally symmetrical primordia that may be of equivalent embryological origin: the anterior lateral plate mesoderm in vertebrates and the dorsal-most mesoderm in arthropods. These mesodermal progenitors then merge into a heart tube at the ventral midline (vertebrates) or the dorsal midline (Drosophila). These observations suggest that there may be similarities between vertebrate and invertebrate heart development. The homeobox gene, tinman, is required for heart as well as visceral mesoderm formation in Drosophila, and at least one of several vertebrate genes with similarities in protein sequence and cardiac expression to tinman is crucial for heart development in vertebrates. Inductive signals are also required for Drosophila heart development: The secreted gene product of wingless (wg) is critical for heart development during a time period distinct from its function in segmentation and neurogenesis. Here, we show that wg is epistatic to hedgehog (hh), another secreted segmentation gene product, in its requirement for heart formation. We also provide evidence show that downstream of wg in the signal transduction cascade, dishevelled (dsh, a pioneer protein) and armadillo (arm, [Beta]-catenin homolog) are mediating the cardiogenic Wg signal. In particular, overexpression of dsh can restore heart formation in the absence of wg function. We discuss the possibility that Wg signaling is part of a combinatorial mechanism to specify the cardiac mesoderm.

Keshan disease is an endemic fatal dilated cardiomyopathy that can cause heart enlargement, heart failure, and cardiogenic death. Selenium deficiency is considered to be the main cause of Keshan disease. However, the molecular mechanism underlying Keshan disease remains unclear. Our whole-exome sequencing from 68 patients with Keshan disease and 100 controls found 199 candidate genes by gene-level burden tests. Interestingly, using multiomics data, the selenium-related gene ALAD (δ-aminolevulinic acid dehydratase) was the only candidate causative gene identified by three different analysis approaches. Based on single-cell transcriptome data, ALAD was highly expressed in cardiomyocytes and double mutations of human ALAD dramatically reduced its enzyme activity in vitro compared to negative control. Functional analysis of ALAD inhibition in mice resulted in a Keshan phenotype with left ventricular enlargement and cardiac dysfunction, whereas administration of sodium selenite markedly reversed the changes caused by ALAD inhibition. In addition, sodium selenite reversed Keshan phenotypes by affecting energy metabolism and mitochondrial function in mice as shown by the transcriptomic and proteomic data and the ultrastructure of cardiac myocytes. Our findings are the first to demonstrate that the selenium-related gene ALAD is essential for cardiac function by maintaining normal mitochondrial activity, providing strong molecular evidence supporting the hypothesis of selenium deficiency in Keshan disease. These results identified ALAD as a novel target for therapeutic intervention in Keshan disease and Keshan disease-related dilated cardiomyopathy. Blood samples were collected and analyzed with whole-exome sequencing from 68 patients with Keshan disease and 100 healthy individuals, and the selenium-related gene ALAD is the only candidate pathogenic gene identified by three different analysis approaches. The inhibition of ALAD in mice promoted left ventricular enlargement and cardiac dysfunction, but the addition of sodium selenite remarkably reserved the changes caused by inhibition of ALAD. Our data showed that a large number of proteins associated with energy metabolism were upregulated and mitochondrial function was impaired by ALAD inhibition, while widespread upregulated proteins were returned to normal expression with the addition of sodium selenite. [Display omitted] • Selenium-related gene ALAD is a novel target for therapeutic intervention in Keshan disease. • ALAD inhibition in mice resulted in left ventricular enlargement and cardiac dysfunction, and sodium selenite reversed KD phenotypes. [ABSTRACT FROM AUTHOR]

Spring viremia of carp virus (SVCV) causes severe morbidity and mortality in grass carp (Ctenopharyngodon idellus) in Europe, America and several Asian countries. We found that FKBP5 (FK506-binding protein 5) is an SVCV infection response factor; however, its role in the innate immune mechanism caused by SVCV infection remains unknown. This study cloned gcFKBP5 (grass carp FKBP5) and made its mimic protein structure for function discussion. We found that gcFKBP5 expression in the primary innate immune organs of grass carp, including intestine, liver and spleen, was highly upregulated by SVCV in 24 h, with a similar result in fish cells by poly(I:C) treatment. gcFKBP overexpression aggravates viral damage to cells and increases viral replication. Furthermore, SVCV engages gcFKBP5 interacting with TRAF2 (tumour necrosis factor receptor-associated factor 2) to promote host cell apoptosis for supporting viral replication. The enhanced viral replication seems not to be due to the repression of IFN and other antiviral factors as expected. For the first time, these data show the pivotal role of gcFKBP5 in the innate immune response of grass carp to SVCV infection. ●We cloned the gene sequence of grass carp FKBP5(gcFKBP5) for the first time and constructed the related expression vector. ●gcFKBP5 was activated in the immune organs of grass carp. ●Over-expression of gcFKBP5 aggravated the damage of virus infection and increased the replication of virus. ●gcFKBP5 interacted with TRAF2 during viral replication. ●gcFKBP5 did not inhibit IFN or other antiviral factors production during virus infection. [ABSTRACT FROM AUTHOR]

Abstract: p63 is a transcription factor homologous to p53 and p73; mutations in this gene have been identified in individuals with several types of developmental abnormalities, including EEC (ectrodactyly, ectodermal dysplasia, facial clefts) syndrome and split-hand/split-foot malformation (SHFM). Several mutations in the p63 gene have previously been shown to be related to SHFM. In this study, we report on a Chinese family with intrafamilial clinical variability of SHFM that have a novel heterozygous mutation in all four affected individuals. The mutation is in exon 8 of p63, 1046G→A, which predicts an amino acid substitution G310E. SSCP analysis of the segregation pattern of the mutation strongly suggests a causal relationship to the SHFM phenotype in p63. This mutation has not been observed in other countries in the world. [Copyright &y& Elsevier]

Abstract: The Drosophila heart has proven itself to be an excellent model for human cardiac development and recent investigations suggest that it may serve as a model for human heart function as well. Just as tinman-related genes underlie cardiac development in all organisms with a heart, the functional properties of mature hearts also appear to be conserved in the animal kingdom. Ion channels, such as those encoded by the potassium channel genes KCNQ and HERG, contribute to normal heart function in humans and flies, and when malfunctioning, cause cardiomyopathies or arrhythmias in remarkably similar ways in both species. Moreover, the KATP channel encoded by dSUR protects the heart against hypoxia/ischemia in flies and mammals, and this protection seems to be reduced with age. Indeed, aging appears to affect heart function and performance in flies in ways that are reminiscent of the decline in human heart function with age, and this likely includes a cardiac autonomous function for the insulin-signaling pathway. The potential for discovery of new genes, such as the two-pore ORK1 K+ channel that affects heart rate in flies, makes Drosophila an attractive heart model for genome-wide screens and for complex genetic manipulations needed to elucidate the mechanisms contributing to cardiac malfunction. Insights gained from the fly heart may prove to be instrumental in unraveling the mysteries of the human heart in health and disease. [Copyright &y& Elsevier]

Abstract: Camurati–Engelmann disease (CED) [OMIM 131300] is a rare autosomal dominant disorder characterized by bone pain and osteosclerosis affecting the diaphysis of long bones. It has been previously reported that CED is caused by mutations of the transforming growth factor beta 1 (TGFβ1) gene on chromosome 19q13.1–q13.3. Until now, seven mutations (LLL12-13ins, Y81H, R156C, R218C, R218H, H222D, C225R) in Australian, French, Belgian, Japanese, and European families have been reported and these data showed that there was no correlation between the nature of the mutations and the variability of the clinical manifestations. In this study, we found a Chinese family with CED and observed some intra-familial clinical variability and symptoms that became more severe with the age. A new TGFβ1 mutation (E169K) in exon 2 was identified in the Chinese family using polymerase chain reaction, direct sequencing analysis of PCR products and single-strand conformation polymorphism analysis. This mutation has not been previously reported in other countries in the world. [Copyright &y& Elsevier]