Innate versus learned odour processing in the mouse olfactory bulb

The mammalian olfactory system mediates various responses, including aversive behaviours to spoiled foods and fear responses to predator odours. In the olfactory bulb, each glomerulus represents a single species of odorant receptor. Because a single odorant can interact with several different receptor species, the odour information received in the olfactory epithelium is converted to a topographical map of multiple glomeruli activated in distinct areas in the olfactory bulb. To study how the odour map is interpreted in the brain, we generated mutant mice in which olfactory sensory neurons in a specific area of the olfactory epithelium are ablated by targeted expression of the diphtheria toxin gene. Here we show that, in dorsal-zone-depleted mice, the dorsal domain of the olfactory bulb was devoid of glomerular structures, although second-order neurons were present in the vacant areas. The mutant mice lacked innate responses to aversive odorants, even though they were capable of detecting them and could be conditioned for aversion with the remaining glomeruli. These results indicate that, in mice, aversive information is received in the olfactory bulb by separate sets of glomeruli, those dedicated for innate and those for learned responses.     

Fras1 deficiency results in cryptophthalmos,renal agenesis and blebbed phenotype in mice

Loss of tight association between epidermis and dermis underlies several blistering disorders and is frequently caused by impaired function of extracellular matrix (ECM) proteins. Here we describe a new protein in mouse, Fras1, that is specifically detected in a linear fashion underlying the epidermis and the basal surface of other epithelia in embryos. Loss of Fras1 function results in the formation of subepidermal hemorrhagic blisters as well as unilateral or bilateral renal agenesis during mouse embryogenesis. Postnatally, homozygous Fras1 mutants have fusion of the eyelids and digits and unilateral renal agenesis or dysplasia. The defects observed in Fras1-/- mice phenocopy those of the existing bl (blebbed) mouse mutants, which have been considered a model for the human genetic disorder Fraser syndrome. We show that bl/bl homozygous embryos are devoid of Fras1 protein, consistent with the finding that Fras1 is mutated in these mice. In sum, our data suggest that perturbations in the composition of the extracellular space underlying epithelia could account for the onset of the blebbed phenotype in mouse and Fraser syndrome manifestation in human.     

Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancer

Aberrant WNT pathway signaling is an early progression event in 90% of colorectal cancers. It occurs through mutations mainly of APC and less often of CTNNB1 (encoding beta-catenin) or AXIN2 (encoding axin-2, also known as conductin). These mutations allow ligand-independent WNT signaling that culminates in abnormal accumulation of free beta-catenin in the nucleus. We previously identified frequent promoter hypermethylation and gene silencing of the genes encoding secreted frizzled-related proteins (SFRPs) in colorectal cancer. SFRPs possess a domain similar to one in the WNT-receptor frizzled proteins and can inhibit WNT receptor binding to downregulate pathway signaling during development. Here we show that restoration of SFRP function in colorectal cancer cells attenuates WNT signaling even in the presence of downstream mutations. We also show that the epigenetic loss of SFRP function occurs early in colorectal cancer progression and may thus provide constitutive WNT signaling that is required to complement downstream mutations in the evolution of colorectal cancer.     

Visual pigment: G-protein-coupled receptor for light signals

The visual pigment present in photoreceptor cells is a prototypical G-protein-coupled receptor (GPCR) that receives a light signal from the outer environment using a light-absorbing chromophore, 11-cis-retinal. Through cis-trans isomerization of the chromophore, light energy is transduced into chemical free energy, which is in turn utilized for conformational changes in the protein to activate the retinal G-protein. In combination with site-directed mutagenesis, various spectroscopic and biochemical studies identified functional residues responsible for chromophore binding, color regulation, intramolecular signal transduction and G-protein coupling. Extensive studies reveal that these residues are localized into specific domains of visual pigments, suggesting a highly manipulated molecular architecture in visual pigments. In addition to the recent findings on dysfunctional mutations in patients with retinitis pigmentosa or congenital night blindness, the mechanism of intramolecular signal transduction in visual pigments and their evolutionary relationship are discussed. Received 20 July 1998; received after revision 9 September 1998; accepted 23 September 1998     

Evidence for dissociation of ferrihemoglobin by poly-L-lysine

Summary Circular dichroism and absorption spectra of ferrihemoglobin were shown to be altered upon binding with poly-L-lysine at alkaline pH. When ferrihemoglobin immobilized to Sepharose gel was treated with poly-L-lysine, hemoglobin subunits were released from the gel. These results suggest that ferrihemoglobin was dissociated into subunits by poly-L-lysine.We thank Dr A. Ichihara and K. Aki for their valuable discussions and encouragement during the course of these studies.     

Epstein-Barr virus genome-positive T lymphocytes in a boy with chronic active EBV infection associated with Kawasaki-like disease

Epstein-Barr virus (EBV), a ubiquitous human herpesvirus and an aetiological agent of infectious mononucleosis, has a unique tropism for B lymphocytes. Clinical and laboratory features of chronic active EBV infections are chronic or persistent infectious mononucleosis-like symptoms and high antibody titre against early antigens (EA). Kawasaki disease (KD), aetiology unknown, is thought to be self-limited immunologically mediated vasculitis. Clinical features of KD are fever, rash, mucositis, lymphadenopathy and coronary artery damage. We report here a child with chronic active EBV infection accompanied by dilatation of coronary arteries. All the EBV-determined nuclear antigen (EBNA)-positive lymphocytes had exclusively CD4 antigen, as revealed by dual staining immunofluorescence analysis. Southern blot hybridization showed that the purified CD4+ cells harboured EBV genome.     

Epidermal growth factor stimulates proliferation of rat hepatoma cells producing alpha-fetoprotein.

Epidermal growth factor stimulated both [3H]thymidine uptake and proliferation of rat AH66 hepatoma cells. However, the increase in cell number was not accompanied by a proportional increase in the levels of alpha-fetoprotein of the culture media. The effects of EGF on the cell proliferation were antagonized by N6,O2'-dibutyryl cAMP.     

Sandwich enzyme immunoassay of mouse mammary tumor virus

Summary A highly sensitive sandwich enzyme immunoassay for the mouse mammary tumor virus (MMTV) is described. The assay can detect 3 ng/ml of MMTV. The enzyme used is ß-D-galactosidase fromEscherichia coli and the solid phase used is a piece of silicon rubber.     

Stimulation of human chorionic gonadotropin and progesterone secretion by tumor promoters,phorbol ester and teleocidin B,in cultured choriocarcinoma cells

Summary Both 12-O-tetradecanoyl-phorbol-1-acetate and teleocidin B stimulated the secretion of human chorionic gonadotropin by cultured choriocarcinoma cells. These tumor promoters also stimulated production of progesterone in the cells. However, the 2 tumor promoters did not exert a marked effect on the cellular binding of epidermal growth factor that also had a stimulatory effect on production of these hormones.