The ciliary gene RPGRIP1L is mutated in cerebello-oculo-renal syndrome (Joubert syndrome type B) and Meckel syndrome

Cerebello-oculo-renal syndrome (CORS), also called Joubert syndrome type B, and Meckel (MKS) syndrome belong to the group of developmental autosomal recessive disorders that are associated with primary cilium dysfunction. Using SNP mapping, we identified missense and truncating mutations in RPGRIP1L (KIAA1005) in both CORS and MKS, and we show that inactivation of the mouse ortholog Rpgrip1l (Ftm) recapitulates the cerebral, renal and hepatic defects of CORS and MKS. In addition, we show that RPGRIP1L colocalizes at the basal body and centrosomes with the protein products of both NPHP6 and NPHP4, known genes associated with MKS, CORS and nephronophthisis (a related renal disorder and ciliopathy). In addition, the RPGRIP1L missense mutations found in CORS individuals diminishes the interaction between RPGRIP1L and nephrocystin-4. Our findings show that mutations in RPGRIP1L can cause the multiorgan phenotypic abnormalities found in CORS or MKS, which therefore represent a continuum of the same underlying disorder.     

Formation of accumbens GluR2-lacking AMPA receptors mediates incubation of cocaine craving

Relapse to cocaine use after prolonged abstinence is an important clinical problem. This relapse is often induced by exposure to cues associated with cocaine use. To account for the persistent propensity for relapse, it has been suggested that cue-induced cocaine craving increases over the first several weeks of abstinence and remains high for extended periods. We and others identified an analogous phenomenon in rats that was termed 'incubation of cocaine craving': time-dependent increases in cue-induced cocaine-seeking over the first months after withdrawal from self-administered cocaine. Cocaine-seeking requires the activation of glutamate projections that excite receptors for alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) in the nucleus accumbens. Here we show that the number of synaptic AMPA receptors in the accumbens is increased after prolonged withdrawal from cocaine self-administration by the addition of new AMPA receptors lacking glutamate receptor 2 (GluR2). Furthermore, we show that these new receptors mediate the incubation of cocaine craving. Our results indicate that GluR2-lacking AMPA receptors could be a new target for drug development for the treatment of cocaine addiction. We propose that after prolonged withdrawal from cocaine, increased numbers of synaptic AMPA receptors combined with the higher conductance of GluR2-lacking AMPA receptors causes increased reactivity of accumbens neurons to cocaine-related cues, leading to an intensification of drug craving and relapse.     

Strong genetic differentiation among neighboring populations of a locally endemic primrose

Maguire primrose is a locally endemic plant of northern Utah, USA, with a total known range of less than 20 km 2 . A previous study found evidence for strong differentiation among local populations at 4 allozyme loci. Here we reexamined populations using 165 AFLP loci and found further evidence of unusually strong genetic structure. We also found an apparently fixed nucleotide difference between populations for a noncoding region of chloroplast DNA, mirroring the patterns seen for AFLP loci. Furthermore, we tested the hypothesis that the current population structure is the result of breeding barriers between plants from different populations. We made controlled hand-pollinated crosses and found that interpopulation crosses did not set significantly fewer seeds than intrapopulation crosses. Thus, we found no evidence of breeding barriers to explain these genetic patterns. However, we did note a relatively short overlap in flowering time, suggesting that phenology is a more feasible explanation for genetic differentiation than pollen-stigma incompatibility. Our study emphasizes that even locally endemic plants can house measurable genetic differences over a short geographic scale.     

Wnt-Ryk signalling mediates medial-lateral retinotectal topographic mapping

Computational modelling has suggested that at least two counteracting forces are required for establishing topographic maps. Ephrin-family proteins are required for both anterior-posterior and medial-lateral topographic mapping, but the opposing forces have not been well characterized. Wnt-family proteins are recently discovered axon guidance cues. We find that Wnt3 is expressed in a medial-lateral decreasing gradient in chick optic tectum and mouse superior colliculus. Retinal ganglion cell (RGC) axons from different dorsal-ventral positions showed graded and biphasic response to Wnt3 in a concentration-dependent manner. Wnt3 repulsion is mediated by Ryk, expressed in a ventral-to-dorsal decreasing gradient, whereas attraction of dorsal axons at lower Wnt3 concentrations is mediated by Frizzled(s). Overexpression of Wnt3 in the lateral tectum repelled the termination zones of dorsal RGC axons in vivo. Expression of a dominant-negative Ryk in dorsal RGC axons caused a medial shift of the termination zones, promoting medially directed interstitial branches and eliminating laterally directed branches. Therefore, a classical morphogen, Wnt3, acting as an axon guidance molecule, plays a role in retinotectal mapping along the medial-lateral axis, counterbalancing the medial-directed EphrinB1-EphB activity.     

Identification of the primary gene defect at the cytochrome P450 CYP2D locus

The mammalian cytochrome P450-dependent monooxygenase system is involved in the metabolism of drugs and chemical carcinogens. The role of these enzymes in toxicological response is exemplified by an autosomal recessive polymorphism at the cytochrome P450 CYP2D6 debrisoquine hydroxylase locus which results in the severely compromised metabolism of at least 25 drugs, and which in some cases can lead to life-threatening side-effects. In addition, this polymorphism, which affects 8-10% of the caucasian population, has been associated with altered susceptibility to lung and bladder cancer. Here we report the identification of the primary mutation responsible for this metabolic defect and the development of a simple DNA-based genetic assay to allow both the identification of most individuals at risk of drug side-effects and clarification of the conflicting reports on the association of this polymorphism with cancer susceptibility.     

(S)-3-p-Methoxyphenyl-3-acetylaminopropan-1-ol, a New Metabolite of an Actinomycete.

(S)-3-p-methoxyphenyl-3-acetamidopropan-1-ol was isolated from cultures of an actinomycete (Streptomyces michiganensis). Its structural determination by spectroscopic means and its synthesis are described.     

Transgenes as probes for active chromosomal domains in mouse development

Embryonic development entails a well defined temporal and spatial programme of gene expression, which may be influenced by active chromosomal domains. These chromosomal domains can be detected using transgenes which integrate randomly throughout the genome, as their expression can be affected by chromosomal position. Position effects are probably exerted most strongly on transgenes that do not contain strong promoters, enhancers or other modulating sequences. Here we have systematically explored position effects using a transgene with the weak herpes-simplex-virus thymidine-kinase promoter, linked to the readily visualized lacZ indicator gene (HSV-TK-lacZ). Each transgenic fetus with detectable expression displayed a unique lacZ staining pattern. Thus expression of this construct is apparently dictated entirely by its chromosomal position, without any construct specificity. Furthermore the transgene is faithfully transmitted to subsequent generations, allowing for systematic mapping of changes in expression during development and in adult life. These results demonstrate that transgenes can indeed be powerful tools to probe the genome for active chromosomal regions, with the potential for identifying endogenous genes involved in organogenesis and pattern formation.     

Meaningfulness: A Third Dimension of the Good Life

This paper argues that an adequate conception of a good life should recognize, in addition to happiness and morality, a third dimension of meaningfulness. It further proposes that we understand meaningfulness as involving both a subjective and an objective condition, suitably linked. Meaning arises when subjective attraction meets objective attractiveness. In other words one’s life is meaningful insofar as one is gripped or excited by things worthy of one’s love, and one is able to do something positive about it. The paper concludes with some speculations about how this conception of meaningfulness might help to explain the conditions under which social volunteering can be especially rewarding.