The Fat Cadherin Acts through the Hippo Tumor-Suppressor Pathway to Regulate Tissue Size

Background: The Hippo tumor-suppressor pathway has emerged as a key signaling pathway that controls tissue size in Drosophila. Merlin, the Drosophila homolog of the human Neurofibromatosis type-2 (NF2) tumor-suppressor gene, and the related protein Expanded are the most upstream components of the Hippo pathway identified so far. However, components acting upstream of Expanded and Merlin, such as transmembrane receptors, have not yet been identified. Results: Here, we report that the protocadherin Fat acts as an upstream component in the Hippo pathway. Fat is a known tumor-suppressor gene in Drosophila, and fat mutants have severely overgrown imaginal discs. We found that the overgrowth phenotypes of fatmutants are similar to those of mutants in Hippo pathway components: fat mutant cells continued to proliferate after wild-type cells stopped proliferating, and fat mutant cells deregulated Hippo target genes such as cyclin E and diap1. Fat acts genetically and biochemically upstream of other Hippo pathway components such as Expanded, the Hippo and Warts kinases, and the transcriptional coactivator Yorkie. Fat is required for the stability of Expanded and its localization to the plasma membrane. In contrast, Fat is not required for Merlin localization, and Fat and Merlin act in parallel in growth regulation. Conclusions: Taken together, our data identify a cell-surface molecule that may act as a receptor of the Hippo signaling pathway

KAYAK-alpha modulates circadian transcriptional feedback loops in Drosophila pacemaker neurons

Circadian rhythms are generated by well-conserved interlocked transcriptional feedback loops in animals. In Drosophila, the dimeric transcription factor CLOCK/CYCLE (CLK/CYC) promotes period (per), timeless (tim), vrille (vri), and PAR-domain protein 1 (Pdp1) transcription. PER and TIM negatively feed back on CLK/CYC transcriptional activity, whereas VRI and PDP1 negatively and positively regulate Clk transcription, respectively. Here, we show that the alpha isoform of the Drosophila FOS homolog KAYAK (KAY) is required for normal circadian behavior. KAY-alpha downregulation in circadian pacemaker neurons increases period length by 1.5 h. This behavioral phenotype is correlated with decreased expression of several circadian proteins. The strongest effects are on CLK and the neuropeptide PIGMENT DISPERSING FACTOR, which are both under VRI and PDP1 control. Consistently, KAY-alpha can bind to VRI and inhibit its interaction with the Clk promoter. Interestingly, KAY-alpha can also repress CLK activity. Hence, in flies with low KAY-alpha levels, CLK derepression would partially compensate for increased VRI repression, thus attenuating the consequences of KAY-alpha downregulation on CLK targets. We propose that the double role of KAY-alpha in the two transcriptional loops controlling Drosophila circadian behavior brings precision and stability to their oscillations

A comparative study of the egg-white proteins of passerine birds

The avian order Passeriformes contains more than 5000 of the approximately 8600 species of living birds….https://elischolar.library.yale.edu/peabody_museum_natural_history_bulletin/1031/thumbnail.jp

Studies on in-vivo erythrocyte sensitization and anaemia in acute Salmonella gallinarum infection of chickens

Factors sensitizing the erythrocytes in-vivo during acute Salmonella gallinarum infection in chickens, the probable mechanism of the associated haemolytic anaemia,and the respective roles played by the phenomena of in-vivo erythrocyte sensitization and the haemolytic episode in the overall pathogenesis of this disease syndrome, were investigated.Detailed pathological study of the blood during the acute disease showed that, at the time of death, the infected chicken had developed a very severe anaemia and leucocytosis. By relating the reticulocyte response and the absolute haematologic values to the gross and histopathological changes in the bone-marrow, spleen and the liver, it was shown that the anaemia observed was not of the dyshaemopoeitic type; it was, however, macrocytic and normochromic.It was observed that the erythrocytes regularly became sensitized in-vivo during infection and this was subsequently shown to be a common occurring phenomenon in this disease. By examining the biologic, serologic, immunologic, immunochemical and electrophoretic properties of these in-vivo sensitizing factor(s) it was conclusively established that these factors were specific bacterial 1ipo-polysaccharide and its homologous antibody.Examination of the patterns of sensitization revealed 4 types of in-vivo erythrocyte sensitization, which were found to be intimately related to the severity and mortality of the haemolytic and the disease syndromes respectively. It was also shown that, chickens in which erythrocyte sensitization was detected, a characteristic binodal erythrocyte fragility curve could be demonstrated.Techniques were developed for obtaining from infected animals.. [Page missing]... destruction. It was demonstrated that the sensitized cells recovered from infected animals may consist of a mixed, heterogeneous cell population of a small minority of •maximally' sensitized erythrocytes and a larger number of non-sensitized reticulocytes .Normal chicken serum was found to contain a high con¬ centration of heat-stable, non-gamrna globulin components which inhibit erythrocyte sensitization by bacterial polysaccharide. These inhibitors, determined to act by either neutralising or altering the polysaccharide in such a way as to prevent its sub¬ sequent adsorption by the erythrocyte, were also shown to be signi ficantly decreased in concentration at the peak of the haemolytic episode during acute fowl typhoid.A moderately severe imrnuno-haemolytic anaemia could be induced in chickens by single or multiple injections of endotoxin; evidence for the unequivocal participation of specific antibody in the production of this .anaemia was obtained by challenging endotoxin-injected chickens with homologous anti-endotoxin antibody.The significance of the anaemia in the overall pathogenesis of this infection was investigated and it was shown that the anaemia per se did not increase the susceptibility of the chicken to endotoxin. However, prior intravenous administration of invivo sensitized, homologous or normal, heterologous erythrocytes markedly decreased the of the subsequently injected endotoxin. This latter increase in susceptibility to endotoxin . was suggested to be due to a blockaded reticulo-endothelial system, resulting from increased phagocytosis of the foreign and altered homologous erythrocytes.These results were discussed in relation to the immunological basis of the mechanism of the anaemia and the significance of this anaemia in the overall pathogenesis of this disease syndrome. It was submitted that they were consistent with the hypothesis that the anaemia is the consequence of an immune reaction, involving the specific bacterial polysaccharide and homologous antibody. Furthermore, the anaemia plays an extremely important role in the pathogenesis of the fowl typhoid syndrome.The possibility that similar phenomena and iinnunologic mechanisms may be occurring in other acute gram-negative bacterial infections was also stressed