Expression of stabilized β-catenin in differentiated neurons of transgenic mice does not result in tumor formation

BACKGROUND: Medulloblastomas, embryonal tumors arising in the cerebellum, commonly contain mutations that activate Wnt signaling. To determine whether increased Wnt signaling in the adult CNS is sufficient to induce tumor formation, we created transgenic mice expressing either wild-type or activated β-catenin in the brain. METHODS: Wild-type and mutant human β-catenin transgenes were expressed under the control of a murine PrP promoter fragment that drives high level postnatal expression in the CNS. Mutant β-catenin was stabilized by a serine to phenylalanine alteration in codon 37. RESULTS: Expression of the mutant transgene resulted in an approximately two-fold increase in β-catenin protein levels in the cortex and cerebellum of adult animals. Immunohistochemical analysis revealed nuclear β-catenin in hippocampal, cortical and cerebellar neurons of transgenic animals but not in non-transgenic controls. Tail kinking was observed in some transgenic animals, but no CNS malformations or tumors were detected. CONCLUSIONS: No tumors or morphologic alterations were detected in the brains of transgenic mice expressing stabilized β-catenin, suggesting that postnatal Wnt signaling in differentiated neurons may not be sufficient to induce CNS tumorigenesis

Saving lives in road traffic—ethical aspects

Aim: This article aims at giving an overview of five ethical problem areas relating to traffic safety, thereby providing a general framework for analysing traffic safety from an ethical perspective and encouraging further discussion concerning problems, policies and technology in this area. Subjects and methods: The problems presented in the article are criminalisation, paternalism, privacy, justice and responsibility, and the reasons for choosing these are the following. First, they are all important areas in moral philosophy. Second, they are fairly general and it should be possible to categorise more specific problems under these headings. Ethical aspects of road traffic have not received the philosophical attention they deserve. Every year, more than 1 million people die globally in traffic accidents, and 20 to 50 million people are injured. Ninety per cent of the road traffic fatalities occur in low- and middle-income countries, where it is a growing problem. Politics, economics, culture and technology affect the number of fatalities and injuries, and the measures used to combat deaths in traffic as well as the role of road traffic should be ethically scrutinised. The topics are analysed and discussed from a moral-philosophical perspective, and the discussion includes both theory and applications. Results and conclusion: The author concludes with some thoughts on how the ethical discussion can be included in the public debate on how to save lives in road traffic. People in industrialised societies are so used to road traffic that it is almost seen as part of nature. Consequently, we do not acknowledge that we can introduce change and that we can affect the role we have given road traffic and cars. By acknowledging the ethical aspects of road traffic and illuminating the way the choices society makes are ethically charged, it becomes clear that there are alternative ways to design the road traffic system. The most important general conclusion is that discussion concerning these alternative ways of designing the system should be encouraged

A Novel Signaling Pathway Mediated by the Nuclear Targeting of C-Terminal Fragments of Mammalian Patched 1

Background: Patched 1 (Ptc1) is a polytopic receptor protein that is essential for growth and differentiation. Its extracellular domains accept its ligand, Sonic Hedgehog, while the function of its C-terminal intracellular domain is largely obscure. Principal Findings: In this study, we stably expressed human Ptc1 protein in HeLa cells and found that it is subjected to proteolytic cleavage at the C-terminus, resulting in the generation of soluble C-terminal fragments. These fragments accumulated in the nucleus, while the N-terminal region of Ptc1 remained in the cytoplasmic membrane fractions. Using an anti-Ptc1 C-terminal domain antibody, we provide conclusive evidence that C-terminal fragments of endogenous Ptc1 accumulate in the nucleus of C3H10T1/2 cells. Similar nuclear accumulation of endogenous C-terminal fragments was observed not only in C3H10T1/2 cells but also in mouse embryonic primary cells. Importantly, the C-terminal fragments of Ptc1 modulate transcriptional activity of Gli1. Conclusions: Although Ptc1 protein was originally thought to be restricted to cell membrane fractions, our findings sugges