Hedgehog/Wnt feedback supports regenerative proliferation of epithelial stem cells in bladder

Epithelial integrity in metazoan organs is maintained through the regulated proliferation and differentiation of organ-specific stem and progenitor cells. Although the epithelia of organs such as the intestine regenerate constantly and thus remain continuously proliferative, other organs, such as the mammalian urinary bladder, shift from near-quiescence to a highly proliferative state in response to epithelial injury. The cellular and molecular mechanisms underlying this injury-induced mode of regenerative response are poorly defined. Here we show in mice that the proliferative response to bacterial infection or chemical injury within the bladder is regulated by signal feedback between basal cells of the urothelium and the stromal cells that underlie them. We demonstrate that these basal cells include stem cells capable of regenerating all cell types within the urothelium, and are marked by expression of the secreted protein signal Sonic hedgehog (Shh). On injury, Shh expression in these basal cells increases and elicits increased stromal expression of Wnt protein signals, which in turn stimulate the proliferation of both urothelial and stromal cells. The heightened activity of this signal feedback circuit and the associated increase in cell proliferation appear to be required for restoration of urothelial function and, in the case of bacterial injury, may help clear and prevent further spread of infection. Our findings provide a conceptual framework for injury-induced epithelial regeneration in endodermal organs, and may provide a basis for understanding the roles of signalling pathways in cancer growth and metastasis.     

Experimental infection of bats with Geomyces destructans causes white-nose syndrome

White-nose syndrome (WNS) has caused recent catastrophic declines among multiple species of bats in eastern North America. The disease's name derives from a visually apparent white growth of the newly discovered fungus Geomyces destructans on the skin (including the muzzle) of hibernating bats. Colonization of skin by this fungus is associated with characteristic cutaneous lesions that are the only consistent pathological finding related to WNS. However, the role of G. destructans in WNS remains controversial because evidence to implicate the fungus as the primary cause of this disease is lacking. The debate is fuelled, in part, by the assumption that fungal infections in mammals are most commonly associated with immune system dysfunction. Additionally, the recent discovery that G. destructans commonly colonizes the skin of bats of Europe, where no unusual bat mortality events have been reported, has generated further speculation that the fungus is an opportunistic pathogen and that other unidentified factors are the primary cause of WNS. Here we demonstrate that exposure of healthy little brown bats (Myotis lucifugus) to pure cultures of G. destructans causes WNS. Live G. destructans was subsequently cultured from diseased bats, successfully fulfilling established criteria for the determination of G. destructans as a primary pathogen. We also confirmed that WNS can be transmitted from infected bats to healthy bats through direct contact. Our results provide the first direct evidence that G. destructans is the causal agent of WNS and that the recent emergence of WNS in North America may represent translocation of the fungus to a region with a naive population of animals. Demonstration of causality is an instrumental step in elucidating the pathogenesis and epidemiology of WNS and in guiding management actions to preserve bat populations against the novel threat posed by this devastating infectious disease.     

Cellular internalization of proinsulin C-peptide

Proinsulin C-peptide is known to bind specifically to cell membranes and to exert intracellular effects, but whether it is internalized in target cells is unknown. In this study, using confocal microscopy and immunostained or rhodamine-labeled peptide, we show that C-peptide is internalized and localized to the cytosol of Swiss 3T3 and HEK-293 cells. In addition, transport into nuclei was found using the labeled peptide. The internalization was followed at 37°C for up to 1 h, and was reduced at 4°C and after preincubation with pertussis toxin. Hence, it is concluded to occur via an energy-dependent, pertussis toxin-sensitive mechanism and without detectable degradation within the experimental time course. Surface plasmon resonance measurements demonstrated binding of HEK-293 cell extract components to C-peptide, and subsequent elution of bound material revealed the components to be intracellular proteins. The identification of C-peptide cellular internalization, intracellular binding proteins, absence of rapid subsequent C-peptide degradation and apparent nuclear internalization support a maintained activity similar to that of an intracrine peptide hormone. Hence, the data suggest the possibility of one further C-peptide site of action. Received 31 October 2006; received after revision 27 December 2006; accepted 30 December 2006     

CD24 interacts with and promotes the activity of c-src within lipid rafts in breast cancer cells, thereby increasing integrin-dependent adhesion

Expression of the glycosylphosphatidylinositol-anchored membrane protein CD24 correlates with a poor prognosis for many human cancers, and in experimental tumors can promote metastasis. However, the mechanism by which CD24 contributes to tumor progression remains unclear. Here we report that in MTLy breast cancer cells CD24 interacts with and augments the kinase activity of c-src, a protein strongly implicated in promoting invasion and metastasis. This occurs within and is dependent upon intact lipid rafts. CD24-augmented c-src kinase activity increased formation of focal adhesion complexes, accelerated phosphorylation of FAK and paxillin and consequently enhanced integrin-mediated adhesion. Loss and gain of function approaches showed that c-src activity is necessary and sufficient to mediate the effects of CD24 on integrin-dependent adhesion and cell spreading, as well as on invasion. Together these results indicate that c-src is a CD24-activated mediator that promotes integrin-mediated adhesion and invasion, and suggest a mechanism by which CD24 might contribute to tumor progression through stimulating the activity of c-src or another member of the Src family.     

Visual perception and memory systems: from cortex to medial temporal lobe

Visual perception and memory are the most important components of vision processing in the brain. It was thought that the perceptual aspect of a visual stimulus occurs in visual cortical areas and that this serves as the substrate for the formation of visual memory in a distinct part of the brain called the medial temporal lobe. However, current evidence indicates that there is no functional separation of areas. Entire visual cortical pathways and connecting medial temporal lobe are important for both perception and visual memory. Though some aspects of this view are debated, evidence from both sides will be explored here. In this review, we will discuss the anatomical and functional architecture of the entire system and the implications of these structures in visual perception and memory.     

Altered expression of securin (Pttg1) and serpina3n in the auditory system of hearing-impaired Tff3-deficient mice

Introduction

Tff3 peptide exerts important functions in cytoprotection and restitution of the gastrointestinal (GI) tract epithelia. Moreover, its presence in the rodent inner ear and involvement in the hearing process was demonstrated recently. However, its role in the auditory system still remains elusive. Our previous results showed a deterioration of hearing with age in Tff3-deficient animals.

Results

Present detailed analysis of auditory brain stem response (ABR) measurements and immunohistochemical study of selected functional proteins indicated a normal function and phenotype of the cochlea in Tff3 mutants. However, a microarray-based screening of tissue derived from the auditory central nervous system revealed an alteration of securin (Pttg1) and serpina3n expression between wild-type and Tff3 knock-out animals. This was confirmed by qRT-PCR, immunostaining and western blots.

Conclusions

We found highly down-regulated Pttg1 and up-regulated serpina3n expression as a consequence of genetically deleting Tff3 in mice, indicating a potential role of these factors during the development of presbyacusis.     

Systematics and distribution of the winter stonefly genus Capnia (Plecoptera:Capniidae) in North America

The genus Capnia in North America is reviewed and compared to other genera in the family. The genus is divided into 10 species groups. A key to the 51 species of Capnia in North America is given along with a listing of type localities, type repositories, diagnoses, and distributions. New illustrations of structures bearing characters important for identification and classification are presented. An annotation of the list of Capnia of North America given by Stark, Szczytko, and Baumann (1986) reflecting current generic placement of species is produced. From this list Capnia bakeri and sugluka are moved to Mesocapnia . Capnia barbata Frison is placed in synonymy under Capnia decepta . The movement of cygna (synonym of venosa ), elevata, fibula, manitoba, venosa , and wanica to Capnura (Nelson and Baumann, 1987b) is noted. Capnia disala and ensicala are placed in Paracapnia .     

Stoneflies (Plecoptera) of the Black Hills of South Dakota and Wyoming, USA: distribution and zoogeographic affinities

The Black Hills of South Dakota and Wyoming are an insular mountain range completely surrounded by the Great Plains. The stonefly (Plecoptera) fauna of the Black Hills was surveyed and zoogeographic affinities examined. Twenty-seven species representing 22 genera and 6 families were found. Fifteen new state records for South Dakota and 2 for Wyoming are presented. Two species are removed from the South Dakota list. An analysis of the North American distribution of each species showed a strong relationship between the Black Hills and the Rocky Mountains, with much weaker relationships between the Black Hills and eastern and northern regions. Results of a logistic regression analysis comparing factors contributing to long-distance dispersal ability against presence/absence in the Black Hills were inconclusive. However, other evidence suggests that the Black Hills fauna is a result of expansion and subsequent vicariance of stonefly populations during Pleistocene climatic oscillations.     

Epigenetics: a link between addiction and social environment

The detrimental effects of drug abuse are apparently not limited to individuals but may also impact the vulnerability of their progenies to develop addictive behaviours. Epigenetic signatures, early life experience and environmental factors, converge to influence gene expression patterns in addiction phenotypes and consequently may serve as mediators of behavioural trait transmission between generations. The majority of studies investigating the role of epigenetics in addiction do not consider the influence of social interactions. This shortcoming in current experimental approaches necessitates developing social models that reflect the addictive behaviour in a free-living social environment. Furthermore, this review also reports on the advancement of interventions for drug addiction and takes into account the emerging roles of histone deacetylase (HDAC) inhibitors in the etiology of drug addiction and that HDAC may be a potential therapeutic target at nucleosomal level to improve treatment outcomes.