Progressive Retinal Atrophy in the Border Collie: A new XLPRA

Background

Several forms of progressive retinal atrophy (PRA) segregate in more than 100 breeds of dog with each PRA segregating in one or a few breeds. This breed specificity may be accounted for by founder effects and genetic drift, which have reduced the genetic heterogeneity of each breed, thereby facilitating the identification of causal mutations. We report here a new form of PRA segregating in the Border Collie breed. The clinical signs, including the loss of night vision and a progressive loss of day vision, resulting in complete blindness, occur at the age of three to four years and may be detected earlier through systematic ocular fundus examination and electroretinography (ERG).

Results

Ophthalmic examinations performed on 487 dogs showed that affected dogs present a classical form of PRA. Of those, 274 have been sampled for DNA extraction and 87 could be connected through a large pedigree. Segregation analysis suggested an X-linked mode of transmission; therefore both XLPRA1 and XLPRA2 mutations were excluded through the genetic tests.

Conclusion

Having excluded these mutations, we suggest that this PRA segregating in Border Collie is a new XLPRA (XLPRA3) and propose it as a potential model for the homologous human disease, X-Linked Retinitis Pigmentosa.

     

A cryptic frizzled module in cell surface collagen 18 inhibits Wnt/beta-catenin signaling

Collagens contain cryptic polypeptide modules that regulate major cell functions, such as cell proliferation or death. Collagen XVIII (C18) exists as three amino terminal end variants with specific amino terminal polypeptide modules. We investigated the function of the variant 3 of C18 (V3C18) containing a frizzled module (FZC18), which carries structural identity with the extracellular cysteine-rich domain of the frizzled receptors. We show that V3C18 is a cell surface heparan sulfate proteoglycan, its topology being mediated by the FZC18 module. V3C18 mRNA was expressed at low levels in 21 normal adult human tissues. Its expression was up-regulated in fibrogenesis and in small well-differentiated liver tumors, but decreased in advanced human liver cancers. Low FZC18 immunostaining in liver cancer nodules correlated with markers of high Wnt/beta-catenin activity. V3C18 (M(r) = 170 kD) was proteolytically processed into a cell surface FZC18-containing 50 kD glycoprotein precursor that bound Wnt3a in vitro through FZC18 and suppressed Wnt3a-induced stabilization of beta-catenin. Ectopic expression of either FZC18 (35 kD) or its 50 kD precursor inhibited Wnt/beta-catenin signaling in colorectal and liver cancer cell lines, thus downregulating major cell cycle checkpoint gatekeepers cyclin D1 and c-myc and reducing tumor cell growth. By contrast, full-length V3C18 was unable to inhibit Wnt signaling. In summary, we identified a cell-surface signaling pathway whereby FZC18 inhibits Wnt/beta-catenin signaling. The signal, encrypted within cell-surface C18, is released by enzymatic processing as an active frizzled cysteine-rich domain (CRD) that reduces cancer cell growth. Thus, extracellular matrix controls Wnt signaling through a collagen-embedded CRD behaving as a cell-surface sensor of proteolysis, conveying feedback cues to control cancer cell fate.     

A microfluidic device for temporally controlled gene expression and long-term fluorescent imaging in unperturbed dividing yeast cells

Background

Imaging single cells with fluorescent markers over multiple cell cycles is a powerful tool for unraveling the mechanism and dynamics of the cell cycle. Over the past ten years, microfluidic techniques in cell biology have emerged that allow for good control of growth environment. Yet the control and quantification of transient gene expression in unperturbed dividing cells has received less attention.

Methodology/Principal Findings

Here, we describe a microfluidic flow cell to grow Saccharomyces Cerevisiae for more than 8 generations (≈12 hrs) starting with single cells, with controlled flow of the growth medium. This setup provides two important features: first, cells are tightly confined and grow in a remarkably planar array. The pedigree can thus be determined and single-cell fluorescence measured with 3 minutes resolution for all cells, as a founder cell grows to a micro-colony of more than 200 cells. Second, we can trigger and calibrate rapid and transient gene expression using reversible administration of inducers that control the GAL1 or MET3 promoters. We then show that periodic 10–20 minutes gene induction pulses can drive many cell division cycles with complete coherence across the cell cluster, with either a G1/S trigger (cln1 cln2 cln3 MET3-CLN2) or a mitotic trigger (cdc20 GALL-CDC20).

Conclusions/Significance

In addition to evident cell cycle applications, this device can be used to directly measure the amount and duration of any fluorescently scorable signal-transduction or gene-induction response over a long time period. The system allows direct correlation of cell history (e.g., hysteresis or epigenetics) or cell cycle position with the measured response.     

High frequency palaeoceanographic changes during the past 140?000 yr recorded by the organic matter in sediments of the Iberian Margin

Biogenic records of the marine palaeoproductivity (carbonates, organic carbon, and C₃₇ alkenones) and the molecular stratigraphy of past sea surface temperatures (SSTs; U₃₇^K′) were studied at high resolution in two cores of the Iberian Margin. The comparison of these records indicates that the oceanographic conditions switched abruptly during the past 160 kyr between three kinds of regimes. A first regime with high (17-22°C) SST and low productivity typifies the interglacial periods, marine isotopic stages (MIS) 5 and 1. Several periods during MIS 6, 2, and the terminations II and I are characterised by about 4-5°C colder SST and a higher organic matter accumulation, both of which define the second regime. This anticorrelation between SST and marine productivity suggests that these variations are related to the intensity of the coastal upwelling. By contrast with this upwelling behaviour, extremely low biological productivity and very cold SST (6-12°C) occurred during short phases of glacial MIS 6, 4, and 2, and as abrupt events (≈1 kyr or less) during MIS 3. The three oceanographic regimes are consistent with micropalaeontological changes in the same cores based on foraminifera and diatoms.The general trend of these hydrologic changes follows the long-term glacial/interglacial cycle, but the millennium scale variability is clearly related to Heinrich events and Dansgaard-Oeschger cycles. Strengthening of the upwelling corresponds probably to an intensification of the subtropical atmospheric circulation over the North Atlantic which was influenced by the presence of continental ice sheets. However, extreme glacial conditions due to massive discharges of icebergs interrupted the upwelling. Interestingly, both terminations II and I coincided with strong but transient intensification of the upwelling.     

Key impact of Vgt1 on flowering time adaptation in maize: evidence from association mapping and ecogeographical information

An association study conducted on 375 maize inbred lines indicates a strong relationship between Vgt1 polymorphisms and flowering time, extending former quantitative trait loci (QTL) mapping results. Analysis of allele frequencies in a landrace collection supports a key role of Vgt1 in maize altilatitudinal adaptation.     

The many faces of the SOCS box

The suppressors of cytokine signalling (SOCS) box is a structural domain found at the C-terminus of over 70 human proteins. It is usually coupled to a protein interaction module such as an SH2 domain in case of SOCS proteins, a family of modulators of cytokine signaling. The SOCS box participates in the formation of E3 ligase complexes, marking activated cytokine receptor complexes for proteasomal degradation. A similar mechanism was recently uncovered for controlling SOCS activity itself, since SOCS2 was found to enhance the turnover of other SOCS proteins. The SOCS box can also add unique features to individual SOCS proteins: it can function as an adaptor domain as was demonstrated for SOCS3, or as a modulator of substrate binding in case of CIS. In this review we discuss these multiple roles of the SOCS box, which emerges as a versatile module controlling cytokine signaling via multiple mechanisms.