Mechanism for the learning deficits in a mouse model of neurofibromatosis type 1.

Neurofibromatosis type I (NF1) is one of the most common single-gene disorders that causes learning deficits in humans. Mice carrying a heterozygous null mutation of the Nfl gene (Nfl(+/-) show important features of the learning deficits associated with NF1 (ref. 2). Although neurofibromin has several known properties and functions, including Ras GTPase-activating protein activity, adenylyl cyclase modulation and microtubule binding, it is unclear which of these are essential for learning in mice and humans. Here we show that the learning deficits of Nf1(+/-) mice can be rescued by genetic and pharmacological manipulations that decrease Ras function. We also show that the Nf1(+/-) mice have increased GABA (gamma-amino butyric acid)-mediated inhibition and specific deficits in long-term potentiation, both of which can be reversed by decreasing Ras function. Our results indicate that the learning deficits associated with NF1 may be caused by excessive Ras activity, which leads to impairments in long-term potentiation caused by increased GABA-mediated inhibition. Our findings have implications for the development of treatments for learning deficits associated with NF1.     

Distinct representations of olfactory information in different cortical centres

Sensory information is transmitted to the brain where it must be processed to translate stimulus features into appropriate behavioural output. In the olfactory system, distributed neural activity in the nose is converted into a segregated map in the olfactory bulb. Here we investigate how this ordered representation is transformed in higher olfactory centres in mice. We have developed a tracing strategy to define the neural circuits that convey information from individual glomeruli in the olfactory bulb to the piriform cortex and the cortical amygdala. The spatial order in the bulb is discarded in the piriform cortex; axons from individual glomeruli project diffusely to the piriform without apparent spatial preference. In the cortical amygdala, we observe broad patches of projections that are spatially stereotyped for individual glomeruli. These projections to the amygdala are overlapping and afford the opportunity for spatially localized integration of information from multiple glomeruli. The identification of a distributive pattern of projections to the piriform and stereotyped projections to the amygdala provides an anatomical context for the generation of learned and innate behaviours.     

Differential effects of oncogenic K-Ras and N-Ras on proliferation, differentiation and tumor progression in the colon

Kras is commonly mutated in colon cancers, but mutations in Nras are rare. We have used genetically engineered mice to determine whether and how these related oncogenes regulate homeostasis and tumorigenesis in the colon. Expression of K-Ras(G12D) in the colonic epithelium stimulated hyperproliferation in a Mek-dependent manner. N-Ras(G12D) did not alter the growth properties of the epithelium, but was able to confer resistance to apoptosis. In the context of an Apc-mutant colonic tumor, activation of K-Ras led to defects in terminal differentiation and expansion of putative stem cells within the tumor epithelium. This K-Ras tumor phenotype was associated with attenuated signaling through the MAPK pathway, and human colon cancer cells expressing mutant K-Ras were hypersensitive to inhibition of Raf, but not Mek. These studies demonstrate clear phenotypic differences between mutant Kras and Nras, and suggest that the oncogenic phenotype of mutant K-Ras might be mediated by noncanonical signaling through Ras effector pathways.     

The localization of kallikrein in the dog and guinea-pig submandibular glands

Summary In the dog and guinea-pig submandibular glands kallikrein seems to be present in the striated duct cells. Following sympathetic nerve and in vivo isoproterenol stimulation of the dog and guinea-pig submandibular gland respectively, there is a reduction of kallikrein concentration. Ultrastructurally this reduction corresponds to the decrease of straited duct secretory granules in both species. Parasympathetic stimulation also causes some release of kallikrein from both species.Supported by Dean's M.R.C. grant to the College of Dentistry.     

Plant uptake of aluminium from calcareous soils

Concentrations of Al in leaf tissue of plants growing on limestone soils (pH ca. 8) are similar to, or do not deviate much from, concentrations in plants growing on acid silicate soils. Aluminium concentrations in the topsoil solution are at least one order of magnitude lower in limestone than in acid silicate soils. Plants seem to absorb Al quite efficiently under moderately alkaline soil conditions. Possible mechanisms for this are discussed.     

Extreme deuterium enrichment in stratospheric hydrogen and the global atmospheric budget of H2

Molecular hydrogen (H2) is the second most abundant trace gas in the atmosphere after methane (CH4). In the troposphere, the D/H ratio of H2 is enriched by 120 per thousand relative to the world's oceans. This cannot be explained by the sources of H2 for which the D/H ratio has been measured to date (for example, fossil fuels and biomass burning). But the isotopic composition of H2 from its single largest source--the photochemical oxidation of methane--has yet to be determined. Here we show that the D/H ratio of stratospheric H2 develops enrichments greater than 440 per thousand, the most extreme D/H enrichment observed in a terrestrial material. We estimate the D/H ratio of H2 produced from CH4 in the stratosphere, where production is isolated from the influences of non-photochemical sources and sinks, showing that the chain of reactions producing H2 from CH4 concentrates D in the product H2. This enrichment, which we estimate is similar on a global average in the troposphere, contributes substantially to the D/H ratio of tropospheric H2.     

An oncogenic KRAS2 expression signature identified by cross-species gene-expression analysis

Using advanced gene targeting methods, generating mouse models of cancer that accurately reproduce the genetic alterations present in human tumors is now relatively straightforward. The challenge is to determine to what extent such models faithfully mimic human disease with respect to the underlying molecular mechanisms that accompany tumor progression. Here we describe a method for comparing mouse models of cancer with human tumors using gene-expression profiling. We applied this method to the analysis of a model of Kras2-mediated lung cancer and found a good relationship to human lung adenocarcinoma, thereby validating the model. Furthermore, we found that whereas a gene-expression signature of KRAS2 activation was not identifiable when analyzing human tumors with known KRAS2 mutation status alone, integrating mouse and human data uncovered a gene-expression signature of KRAS2 mutation in human lung cancer. We confirmed the importance of this signature by gene-expression analysis of short hairpin RNA-mediated inhibition of oncogenic Kras2. These experiments identified both a pattern of gene expression indicative of KRAS2 mutation and potential effectors of oncogenic KRAS2 activity in human cancer. This approach provides a strategy for using genomic analysis of animal models to probe human disease.