Hedgehog signalling: how to get from Smo to Ci and Gli

The secreted morphogens of the Hedgehog family have important roles in normal development as well as in associated pathologies, including cancer. The Hedgehog signalling pathway has been studied in Drosophila and is thought to be conserved in vertebrates. Hedgehog elicits a signalling response that activates Smoothened (Smo). There is evidence of differences between Drosophila and vertebrates concerning signalling downstream of Smo, as well as in Smo itself. Here, we discuss this evidence and its importance for investigations of the pathway and related biology, as well as for the development of drugs targeting components of the pathway for treatment of associated pathologies.     

Transplant experiments. Growth-limiting factors for diatoms and bluegreen algae in Norwegian lakes

Population densities and total phosphorus concentrations in samples from different lakes of south-eastern Norway were determined. In addition some transplant experiments with dilute phytoplankton populations were carried out. A laboratory batch culture method was used.The diatoms studied may be divided into three ecological groups based on their cell densities and total phosphorus concentrations in the samples. This classification was supported by the experimental results. Cyclotella spp., Asterionella formosa and Tabellaria fenestrata did not grow or had low growth rates above pH 9. Synedra cf. acus and Fragilaria crontonensis had often high growth rates within the pH 9–10 range, but were not able to grow at pH values above 10. High pH-values had no effect on the growth rate of Oscillatoria. Oscillatoria, Synedra and Stephanodiscus were severely growth-limited in filtered water from oligotrophic lakes. Maximum growth rates of all the populations studied were often obtained after addition of phosphate and chelated iron (FeEDTA) in combination to filtered water samples from oligotrophic/mesotrophic lakes.     

A girl with karyotype 46,XX,del(7) (qter→p15:)

Summary A girl with partial deletion of the short arms of one chromosome 7 is described. Among many other symptoms she has craniosynostosis. Early closure of cranio-sutures has previously been described in 2 of 3 patients with partial deletion 7. Investigation of a number of genetic marker systems shows that the HL-A, MN, AcP, and GPT loci are not located in the deleted segment.

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Zusammenfassung Es wird ein Mädchen mit teilweiser Deletion des kurzen Armes eines Chromosoms 7 beschrieben. Außer vielen anderen Symptomen hat sie eine Craniosynostose. Frühzeitiger Verschluß der Schädelnähte wurde auch bei 2 von 3 Patienten mit Deletion 7, die in der Literatur beschrieben sind, beobachtet. Untersuchung einer Reihe genetischer Markersysteme zeigt, daß die HL-A-, MN-, AcP- und GPT-loci nicht in dem deletierten Segment liegen.

     

snoRNPs Regulate Telomerase Activity in Neuroblastoma and Are Associated with Poor Prognosis

Amplification of the MYCN oncogene is strongly associated with poor prognosis in neuroblastoma (NB). In addition to MYCN amplification, many studies have focused on identifying patients with a poor prognosis based on gene expression profiling. The majority of prognostic signatures today are comprised of large gene lists limiting their clinical application. In addition, although of prognostic significance,most of these signatures fail to identify cellular processes that can explain their relation to prognosis. Here, we determined prognostically predictive genes in a data set containing 251 NBs. Gene Ontology analysis was performed on significant genes with a positive hazard ratio to search for cellular processes associated with poor prognosis. An enrichment in ribonucleoproteins (RNPs) was found. Genes involved in the stabilization and formation of the central small nucleolar RNP (snoRNP) complex were scrutinized using a backward conditional Cox regression resulting in an snoRNP signature consisting of three genes: DKC1, NHP2, and GAR1. The snoRNP signature significantly and independently predicted prognosis when compared to the established clinical risk factors. Association of snoRNP protein expression and prognosis was confirmed using tissue microarrays. Knockdown of snoRNP expression in NB cell lines resulted in reduced telomerase activity and an increase in anaphase bridge frequency. In addition, in patient material, expression of the snoRNP complex was significantly associated with telomerase activity, occurrence of segmental aberrations, and expression-based measurements of chromosomal instability. Together, these results underscore the prognostic value of snoRNP complex expression in NB and suggest a role for snoRNPs in telomere maintenance and genomic stability.     

The involvement of the docking protein Gab1 in mitogenic signalling induced by EGF and HGF in rat hepatocytes

Grb2-assosiated binder (Gab) family proteins are docking molecules that can interact with receptor tyrosine kinases (RTKs) and cytokine receptors and bind several downstream signalling proteins. Studies in several cell types have shown that Gab1 may have a role in signalling mediated by the two RTKs epidermal growth factor (EGF) receptor (EGFR) and Met, the receptor for hepatocyte growth factor (HGF), but the involvement of Gab1 in EGFR and Met signalling has not been directly compared in the same cell. We have studied mechanisms of activation and role in mitogenic signalling of Gab1 in response to EGF and HGF in cultured rat hepatocytes. Gab1, but not Gab2, was expressed in the hepatocytes and was phosphorylated upon stimulation with EGF or HGF. Depletion of Gab1, using siRNA, decreased the ERK and Akt activation, cyclin D1 expression, and DNA synthesis in response to both EGF and HGF. Studies of mechanisms of recruitment to the receptors showed that HGF induced co-precipitation of Gab1 and Met while EGF induced binding of Gab1 to Grb2 but not to EGFR. Gab1 activation in response to both EGF and HGF was dependent on PI3K. While EGF activated Gab1 and Shc equally, within the same concentration range, HGF very potently and almost exclusively activated Gab1, having only a minimal effect on Shc. Collectively, our results strongly suggest that although Gab1 interacts differently with EGFR and Met, it is involved in mitogenic signalling mediated by both these growth factor receptors in hepatocytes.     

Differences in virulence of marine and freshwater isolates of viral hemorrhagic septicemia virus in vivo correlate with in vitro ability to infect gill epithelial cells and macrophages of rainbow trout (Oncorhynchus mykiss)

Two strains of viral hemorrhagic septicemia virus (VHSV) with known different virulence characteristics in vivo were studied (by a time course approach) for their abilities to infect and translocate across a primary culture of gill epithelial cells (GEC) of rainbow trout (RBT; Oncorhynchus mykiss). The strains included one low-virulence marine VHSV (ma-VHSV) strain, ma-1p8, and a highly pathogenic freshwater VHSV (fw-VHSV) strain, fw-DK-3592B. Infectivities toward trout head kidney macrophages were also studied (by a time course method), and differences in in vivo virulence were reconfirmed, the aim being to determine any correlation between in vivo virulence and in vitro infectivity. The in vitro studies showed that the fw-VHSV isolate infected and caused a cytotoxic effect in monolayers of GEC (demonstrating virulence) at an early time point (2 h postinoculation) and that the same virus strain had translocated over a confluent, polarized GEC layer by 2 h postinoculation. The marine isolate did not infect monolayers of GEC, and delayed translocation across polarized GEC was seen by 48 h postinoculation. Primary cultures of head kidney macrophages were also infected with fw-VHSV, with a maximum of 9.5% virus-positive cells by 3 days postinfection, while for the ma-VHSV strain, only 0.5% of the macrophages were positive after 3 days of culture. In vivo studies showed that the fw-VHSV strain was highly virulent for RBT fry and caused high mortality, with classical features of viral hemorrhagic septicemia. The ma-VHSV showed a very low level of virulence (only one pool of samples from the dead fish was VHSV positive). This study has shown that the differences in virulence between marine and freshwater strains of VHSV following the in vivo infection of RBT correlate with in vitro abilities to infect primary cultures of GEC and head kidney macrophages of the same species.     

Determination of growth-limiting nutrients for red species of Oscillatoria and two ‘oligotrophic’ diatoms

Laboratory batch experiments with dilute phytoplankton communities were carried out to determine growth-limiting nutrients and the degree of growth limitation for Asterionella formosa, Hass., Tabellaria fenestrata (Lyngb.) Kütz. and red species of Oscillatoria under specific temperature and light conditions. Water samples from five Norwegian lakes with average epilimnetic total phosphorus concentrations ranging from 5 to 30 µg P per 1 were investigated. Both enrichment and transplant experiments were carried out. In samples from the most oligotrophic lakes (Lake Randsfjorden and Lake Tyrifjorden) phosphorus was found to be the growth-limiting nutrient. In samples from Lake Mjøsa silicate was also growth-limiting for the diatoms, while nitrogen could be limiting for both asterionella and Oscillatoria from Lake Steinsfjorden. Phosphorus was often the only limiting nutrient determined for Oscillatoria in Lake Gjersjøen (the most eutrophic of the lakes). In samples from this lake, however, Asterionella was also growth-limited directly or indirectly as a result of high (pH > 9). This was also found for Asterionella and Tabellaria from lake Mjøsa by means of transplant experiments. Oscillatoria from Lake Gjersjøen could not grow in filtered water from Lake Mjøsa but obtained maximum growth rate after addition of phosphate and chelated iron in combination.     

Successful reproduction and pheromone production by the spruce bark beetle in evolutionary naïve spruce hosts with familiar terpenoid defences

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