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The last decade has evidenced unprecedented progress in gene therapy of Duchenne and Becker muscular dystrophy (DMD and BMD) skeletal muscle disease. Cardiomyopathy is a leading cause of morbidity and mortality in both patients and carriers of DMD, BMD and X-linked dilated cardiomyopathy. However, there is little advance in heart gene therapy. The gene, the vector, vector delivery, the target tissue and animal models are five fundamental components in developing an effective gene therapy. Intensive effort has been made in optimizing gene transfer vectors and methods. Systemic and/or local delivery of recombinant adeno-associated viral vector have resulted in widespread transduction in the rodent heart. The current challenge is to define other parameters that are essential for a successful gene therapy such as the best candidate gene(s), the optimal expression level and the target tissue. This review focuses on these long-ignored aspects and points out future research directions. In particular, we need to address whether all or only some of the recently developed mini- and microgenes are protective in the heart, whether partial correction can lead to whole heart function improvement, whether over-expression is hazardous and whether correcting skeletal muscle disease can slow down or stop the progression of cardiomyopathy. Discussion is also made on whether the current mouse models can meet these research needs.
Hum Mol Genet 2006 Oct 15
PMID:Challenges and opportunities in dystrophin-deficient cardiomyopathy gene therapy. 1698 91

Selenium (Se) is an essential dietary trace element, involved in the process of male reproduction. Best known as an antioxidant, it acts through various selenoproteins viz. glutathione peroxidase, thioredoxin reductase and selenoprotein P. The aim of the present study was to identify the underlying molecular mechanism of Se in regulating spermatogenesis. Different Se status: deficient, adequate and excess Se, were generated in male Balb/c mice by feeding yeast based Se deficient diet, and deficient diet supplemented with Se as sodium selenite (0.2 and 1 ppm Se) respectively for a period of 4 and 8 weeks. Se levels and glutathione peroxidase (GSH-Px) activity were significantly reduced in the Se deficient mice and enhanced in Se supplemented group. Reduction in the number of post-meiotic germ cells viz. spermatids and spermatozoa, were observed in the deficient groups indicating loss in fertility and reproductive ability. cjun and cfos (components of transcription factor AP1) regulate cellular growth and differentiation and also exert a regulatory role in steroidogenesis and spermatogenesis. Changes in the mRNA expression of cjun and cfos were observed. Concomitant with this, western blot revealed that the protein expression profile for both these genes was significantly altered in the Se deficient and Se excess groups. Further immunohistochemical analysis showed that, both these genes had identical cellular localization indicating that they do not work alone but act synergistically as AP1. cjun and cfos expression was greater in the early mitotic stages-spermatogonia and spermatocytes in the Se adequate controls. It decreased in the meiotic stages and then again peaked around the later stages-elongating spermatids and spermatozoa. However in the Se deficient mice, weaker expression was observed in the spermatogonia with a complete absence of expression near the lumen. No visible changes in cjun/cfos expression and immunohistochemical localization were observed in the excess group compared to the Se adequate controls. In conclusion, the present study clearly demonstrates that alteration in Se supply leads to decreased expression pattern for both cJun and cFos in the testicular germ cells which might be responsible for decreased germ cell number, differentiation and reduced fertility and accounts for the mechanism of Se action in regulating spermatogenesis.
Mol Cell Biochem 2006 Nov
PMID:Role of selenium in spermatogenesis: differential expression of cjun and cfos in tubular cells of mice testis. 1706 17

Two mouse strains, AKR/J and SAMP6, were assessed longitudinally for bone mineral density of the spine. They displayed very different time courses of bone accrual, with the SAMP6 strain reaching a plateau for vertebral BMD at 3 months, whereas AKR/J mice continued to increase spine BMD for at least 8 months. Among 253 F(2) progeny of an AKR/JxSAMP6 cross, at 4 months of age, the BMD variance was 5-6% of the mean, vs. 15% for weight. Variance increased with age for every parameter measured, and was generally higher among males. The ratio of 6-month/4-month spine BMDs, termed DeltasBMD, had a normal distribution with 5.7% variance, and was largely independent of spine BMD (R=-0.23) or body weight (R=-0.12) at maturity. Heritability of the DeltasBMD trait was calculated at 0.59. Genetic mapping identified two significant loci, both distinct from those observed for BMD at maturity--implying that different genes regulate skeletal growth vs. remodeling. A locus on the X chromosome, replicated in two mouse F(2) populations (P<10(-4) for combined discovery and confirmation), affects age-dependent BMD change for both spine and the full skeleton. Its position agrees with a very narrow region identified by association mapping for effects on lumbar bone density in postmenopausal women [Parsons CA, Mroczkowski HJ, McGuigan FE, Albagha OM, Manolagas S, Reid DM, et al. Interspecies synteny mapping identifies a quantitative trait locus for bone mineral density on human chromosome Xp22. Hum Mol Genet 2005;14:3141-8]. A second locus, on chromosome 7, was observed in only one cross. Single-nucleotide polymorphisms (SNPs) are highly clustered near these loci, distinguishing the parental strains over only limited spans.
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PMID:A novel locus on the X chromosome regulates post-maturity bone density changes in mice. 1718 55

Canonical Wnt signaling is essential for bone formation. Activation involves binding of secreted members of the Wnt family of proteins with a membrane receptor Frizzled on osteoblasts, an interaction that is facilitated by LRP5/LRP6 co-receptors. LRP5 is known to play a particularly important role in bone formation such that the loss of this protein results in a reduction in osteoblast number, a delay in mineralization and a reduction in peak BMD. During the course of a VDR ChIP-chip analysis we found that 1,25(OH)(2)D(3) could induce binding of the VDR to sites within the Lrp5 gene locus. Importantly, this interaction between 1,25(OH)(2)D(3)-activated VDR and the Lrp5 gene led to both a modification in chromatin structure within the Lrp5 locus and the induction of LRP5 mRNA transcripts in vivo as well as in vitro. One site within Lrp5 was discovered to confer 1,25(OH)(2)D(3) response to a heterologous promoter in osteoblastic cells, permitting both the identification and characterization of the component VDRE. While the regulatory region in Lrp5 was highly conserved in the human genome, the VDRE was not. Our studies show that 1,25(OH)(2)D(3) can enhance the expression of a critical component of the Wnt signaling pathway which is known to impact osteogenesis.
J Steroid Biochem Mol Biol 2007 Mar
PMID:1,25-Dihydroxyvitamin D3 induces expression of the Wnt signaling co-regulator LRP5 via regulatory elements located significantly downstream of the gene's transcriptional start site. 1722 72

Duchenne/Becker muscular dystrophies (D/BMD) are X-linked recessive disorders resulting from dystrophin gene mutations. Intragenic recombination in the dystrophin gene occurs with a high frequency. Therefore, determination of the location and frequency of recombination improves D/BMD carrier detection and prenatal diagnosis in families in which the disease-causing mutation cannot be detected by most conventional methods. We describe herein a linkage analysis performed using a fast method based on capillary gel electrophoresis of fluorescent-labeled amplified alleles of 15 intragenic short tandem repeats spanning the entire dystrophin gene. On characterization of recombination events in 93 unrelated D/BMD families from southern Italy, we mapped 25 intragenic recombinations out of 273 informative meioses analyzed. The terminal regions of a gene are notoriously challenging for linkage analysis because some recombination events could be missed in case of lack of informativeness of the outermost markers. Many recombination events (10/25) identified in this study were located at the terminal regions of the dystrophin gene, and some were found by typing of several informative short tandem repeats located in these regions. Moreover, about 24% of the recombination events found in this study mapped to the 3' region of the gene, in contrast with the low frequency (4 to 15%) reported by others.
J Mol Diagn 2007 Feb
PMID:A larger spectrum of intragenic short tandem repeats improves linkage analysis and localization of intragenic recombination detection in the dystrophin gene: an analysis of 93 families from southern Italy. 1725 37

Transposable elements (TEs), represent a large fraction of the eukaryotic genome. In Drosophila melanogaster, about 20% of the genome corresponds to such middle repetitive DNA dispersed sequences. A fraction of TEs is composed of elements showing a retrovirus-like structure, the LTR-retrotransposons, the first TEs to be described in the Drosophila genome. Interestingly, in D. melanogaster embryonic immortal cell culture genomes the copy number of these LTR-retrotransposons was revealed to be higher than the copy number in the Drosophila genome, presumably as the result of transposition of some copies to new genomic locations [Potter, S.S., Brorein Jr., W.J., Dunsmuir, P., Rubin, G.M., 1979. Transposition of elements of the 412, copia and 297 dispersed repeated gene families in Drosophila. Cell 17, 415-427; Junakovic, N., Di Franco, C., Best-Belpomme, M., Echalier, G., 1988. On the transposition of copia-like nomadic elements in cultured Drosophila cells. Chromosoma 97, 212-218]. This suggests that so many transpositions modified the genome organisation and consequently the expression of targeted genes. To understand what has directed the transposition of TEs in Drosophila cell culture genomes, a search to identify the newly transposed copies was undertaken using 1731, a LTR-retrotransposon. A comparison between 1731 full-length elements found in the fly sequenced genome (y(1); cn(1)bw(1), sp(1) stock) and 1731 full-length elements amplified by PCR in the two cell line was done. The resulting data provide evidence that all 1731 neocopies were derived from a single copy slightly active in the Drosophila genome and subsequently strongly activated in cultured cells; and that this active copy is related to a newly evolved genomic variant (Kalmykova, A.I., et al., 2004. Selective expansion of the newly evolved genomic variants of retrotransposon 1731 in the Drosophila genomes. Mol. Biol. Evol. 21, 2281-2289). Moreover, neocopies are shown to be inserted in different sets of genes in the two cell lines suggesting they might be involved in the biological and physiological differences observed between Kc and S2 cell lines.
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PMID:Amplification of the 1731 LTR retrotransposon in Drosophila melanogaster cultured cells: origin of neocopies and impact on the genome. 1738 90

Blue native polyacrylamide gel electrophoresis (BN-PAGE) employs the dye Coomassie for the labeling of proteins and protein complexes under native conditions. Electrophoresis under native conditions subsequently allows resolution of proteins and protein complexes according to their molecular mass. BN-PAGE can be combined with second gel dimensions. Best known is the two-dimensional (2D)-BN/sodium dodecyl sulfate (SDS)-PAGE system, which allows resolution of subunits of protein complexes. A 2D-BN/BN-PAGE system was developed that proved useful for investigating the substructure of protein complexes and protein supercomplexes. The basis of this 2D system is a variation of the conditions used for the two BN gel dimensions. Here, we present a basic protocol for the analysis of mitochondrial fractions by 2D-BN/BN-PAGE. Because both el dimensions are carried out under native conditions, the 2D-BN/BN system is compatible with in-gel enzyme activity staining.
Methods Mol Biol 2007
PMID:Two-dimensional blue native/blue native polyacrylamide gel electrophoresis for the characterization of mitochondrial protein complexes and supercomplexes. 1831 36

Long considered a disease of post-menopausal women, osteoporosis is increasingly being recognized among the growing population of elderly men. Androgen deficiency may be associated with an increase of bone resorption in elderly men and so, with remodeling imbalance and fracture risk. It is firmly established that androgen withdrawal induced by orchidectomy (ORX) results in decreased bone mass in animal models especially in rodents. The mature rat is the model of choice. Skeletal effects of ORX in rats have been studied at the tissular and cellular level. It induces a decrease of BMD and BV/TV with microarchitecture alterations due to an increased bone remodeling. The present chapter focuses on the ORX surgery in rats and mice.
Methods Mol Biol 2008
PMID:Orchidectomy models of osteoporosis. 1846 15

Best described outside the nervous system, caveolins are structural proteins that form caveolae, functional microdomains at the plasma membrane that cluster related signaling molecules. Caveolin-associated proteins include G protein-coupled receptors and G proteins, receptor tyrosine kinases, as well as protein kinases, ion channels and various other signaling enzymes. Not surprisingly, a wide array of biological disorders are thought to be rooted in caveolin dysfunction. In addition, caveolins traffic and cluster estrogen receptors to caveolae. Interactions between the estrogen receptors ERalpha and ERbeta with caveolins appear critical in many non-neuronal cell types, e.g., disruption of normal function may underlie many forms of breast cancer. Recent findings suggest caveolins may also play an essential role in membrane estrogen receptor function in the nervous system. Not only are they expressed in neurons and glia, but different caveolin isoforms also appear necessary to generate distinct functional signaling complexes. With membrane estrogen receptors responsible for the efficient activation of a multitude of intracellular signaling pathways, which in turn influence a wide variety of nervous system functions, caveolin proteins are poised to act as the central coordinators of these processes.
Mol Cell Endocrinol 2008 Aug 13
PMID:Caveolin proteins and estrogen signaling in the brain. 1850 30

A number of genes preferentially expressed in the retinal pigment epithelium (RPE) are associated with retinal degenerative disease. One of these, BEST1, encodes bestrophin-1, a protein that when mutated causes Best macular dystrophy. As a model for RPE gene regulation, we have been studying the mechanisms that control BEST1 expression, and recently demonstrated that members of the MITF-TFE family modulate BEST1 transcription. The human BEST1 upstream region from -154 to +38 bp is sufficient to direct expression in the RPE, and positive-regulatory elements exist between -154 and -104 bp. Here, we show that the -154 to -104 bp region is necessary for RPE expression in transgenic mice and contains a predicted OTX-binding site (Site 1). Since another non-canonical OTX site (Site 2) is located nearby, we tested the function of these sites using BEST1 promoter/luciferase constructs by in vivo electroporation and found that mutation of both sites reduces promoter activity. Three OTX family proteins - OTX1, OTX2 and CRX - bound to both Sites 1 and 2 in vitro, and all of them increased BEST1 promoter activity. Surprisingly, we found that human and bovine RPE expressed not only OTX2 but also CRX, the CRX genomic region in bovine RPE was hypersensitive to DNase I, consistent with active transcription, and that both OTX2 and CRX bound to the BEST1 proximal promoter in vivo. These results demonstrate for the first time CRX expression in the RPE, and suggest that OTX2 and CRX may act as positive modulators of the BEST1 promoter in the RPE.
Hum Mol Genet 2009 Jan 01
PMID:BEST1 expression in the retinal pigment epithelium is modulated by OTX family members. 1884 47


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