7th international workshop on the CCN family of genes: Nice to be in nice

In this Editorial, I would like to provide our readers with a brief mid-year update about our activities and efforts to bring together researchers working on intercellular signaling proteins at international meetings. The roots emerged about 20 years ago in the discovery of three genes originally designated cyr61, ctgf, and nov. The proteins encoded by these genes were first proposed to constitute a family of proteins (CCN) which now comprises 6 members (CCN1, CCN2, CCN3, CCN4-6) including the wisp proteins. These proteins were recognized to share a striking structural organization and a high degree of identity although they exhibited quite distinct biological properties. After historical considerations regarding the reasons for using the CCN acronym, and how the ICCNS publishing landscape that drove the ICCNS from Cell Communication and Signaling to the Journal of Cell Communication and Signaling, this short update will focus on the 7th edition of the International Workshop on the CCN family of genes to be held in Nice, Oct 16–19, 2013.     

The CCN family of genes: a perspective on CCN biology and therapeutic potential

The CCN family of genes currently comprises six secreted proteins (designated CCN1–6 after Cyr61/CCN1; ctgf/CCN2; Nov/CCN3; WISP1/CCN4; WISP2/CCN5, WISP3/CCN6) with a similar mosaic primary structure. It is now well accepted that CCN proteins are not growth factors but matricellular proteins that modify signaling of other molecules, in particular those associated with the extracellular matrix. CCN proteins are involved in mitosis, adhesion, apoptosis, extracellular matrix production, growth arrest and migration of multiple cell types. Since their first identification as matricellular factors, the CCN proteins now figure prominently in a variety of major diseases and are now considered valid candidates for therapeutic targeting. Dissection of the molecular mechanisms governing the biological properties of these proteins is being actively pursued by an expanding network of scientists around the globe who will meet this year at the 5th International Workshop on the CCN family of Genes, organized by the International CCN Society (http://ccnsociety.com), home for an international cadre of collaborators working in the CCN field.     

Report on the 7th international workshop on the CCN family of genes

In this report, chairs of the 7th International Workshop on the CCN family of Genes, review the progress made in understanding the biological functions of CCN proteins (CCN1, CCN2, CCN3, CCN4, CCN5 and CCN6) with a particular focus on their implications in various pathological conditions, including cancer, fibrosis, diabetes, and cardiovascular diseases.     

Alternative splicing of CCN mRNAs …. it has been upon us

Variant CCN proteins have been identified over the past decade in several normal and pathological situations. The production of CCN truncated proteins have been reported in the case of CCN2(ctgf), CCN3(nov), CCN4(wisp-1) and CCN6(wisp-3). Furthermore, the natural CCN5 is known to miss the C-terminal domain that is present in all other members of the CCN family of proteins. In spite of compelling evidence that assign important biological activities to these truncated CCN variants, their potential regulatory functions have only recently begun to be widely accepted. The report of CCN1(cyr61) intron 3 retention in breast cancer cells now confirms that, in addition to well documented post-translational processing of full length CCN proteins, alternative splicing is to be regarded as another effective way to generate CCN variants. These observations add to a previous bulk of evidence that support the existence of alternative splicing for other CCN genes. It has become clearly evident that we need to recognize these mechanisms as a means to increase the biological diversity of CCN proteins.     

Microhabitat segregation and physiological differences in co-occurring tiger beetle species,Cicindela oregona and Cicindela tranquebarica

Summary The daily movements of two co-occurring tiger beetle species were monitored in conjunction with changes in microclimate along streams in Northeast Arizona. Cicindela oregona and C. tranquebarica temporarily segregated across areas of beach exhibiting different microclimates. C. oregona progressively moved from the dry upper beach to the wet stream edge as beach temperatures increased and humidity decreased. The actively foraged throughout the day in this moist habitat at air temperatures between 25 and 38°C. C. tranquebarica remained on the dry, upper portions of the beach and shuttled between sun and shade at air temperatures above 35°C. Only when stream edge temperatures exceeded 30°C was tranquebarica found in this subhabitat. Both species exhibited physiological tolerances in the laboratory that were consistent with their microhabitat preferences in the field. Although both species had similar high lethal temperatures (47–48°C) in saturated air, oregona died at lower temperatures (39–43°C) than tranquebarica (46–47°C) under dry (0% RH) conditions. C. oregona was considerably more active than tranquebarica at body temperatures below 30°C and exhibited higher levels of active metabolism between 25 and 40°C. In addition, C. tranquebarica exhibited significantly lower water loss rates than oregona at 30, 35 and 40°C.     

Proteins on the catwalk: modelling the structural domains of the CCN family of proteins

The CCN family of proteins (CCN1, CCN2, CCN3, CCN4, CCN5 and CCN6) are multifunctional mosaic proteins that play keys roles in crucial areas of physiology such as angiogenesis, skeletal development tumourigenesis, cell proliferation, adhesion and survival. This expansive repertoire of functions comes through a modular structure of 4 discrete domains that act both independently and in concert. How these interactions with ligands and with neighbouring domains lead to the biological effects is still to be explored but the molecular structure of the domains is likely to play an important role in this. In this review we have highlighted some of the key features of the individual domains of CCN family of proteins based on their biological effects using a homology modelling approach.     

CCN6 (WISP3): a new anti-cancer therapy?

The CCN family of matricellular proteins are dysregulated in cancers, and may strategies targeting them may represent novel approaches to treating these diseases. A recent study from Huang and colleagues (Cancer Res. 70: 3340-50, 2010) suggests that CCN6 (WISP3) is downregulated in aggressive breast cancers, and this phenomenon may result in the promotion of tumor survival. CCN6 may represent a novel therapeutic approach to breast cancer.     

Yin and Yang revisited: CCN3 as an anti-fibrotic therapeutic?

Fibrotic diseases are a significant cause of mortality. It is being increasingly appreciated that the cellular microenvironment plays a key role in promoting pathological fibrosis. A previous Bits and Bytes described an elegant series of experiments published by Bruce Riser and colleagues (Am J Pathol. 2009: 174:1725–34) that showed that CCN3 (nov) antagonizes the fibrogenic effects of CCN2.and hence could represent a novel anti-fibrotic therapy. They have continued their excellent work and have recently used the ob/ob mouse as a model of obesity and diabetic nephropathy to show that CCN3 could block the induction of profibrotic gene expression, fibrosis and loss of kidney function (Am J Pathol. 2014;184:2908–21). Also, reversal of fibrosis was observed. Thus this paper provides strong evidence that CCN3 may be used as a novel therapy to treat diabetes caused by obesity.     

CCN3-mediated promotion of sulfated proteoglycan synthesis in rat chondrocytes from developing joint heads

Chondrocytes forming articular cartilage are embedded in a vast amount of extracellular matrix having physical stiffness and elasticity, properties that support the mechanical load from bones and enable the flexible movement of synovial joints. Unlike chondrocytes that conduct the growth of long bones by forming the growth plate, articular chondrocytes show suppressed cell proliferation, unless these cells are exposed to pathological conditions such as mechanical overload. In the present study, we found that one of the members of the CCN family, CCN3, was significantly expressed in chondrocytes isolated from the epiphyseal head in developing rat synovial joints. Evaluation of the effect of recombinant CCN3 on those chondrocytes revealed that CCN3 promoted proteoglycan synthesis, whereas this factor repressed the proliferation of the same cells. These results suggest a critical role for CCN3 in the regulation of the biological properties of articular chondrocytes.     

Indian Science for Indian Tigers?: Conservation Biology and the Question of Cultural Values

The implementation of Project Tiger in India, 1973–1974, was justly hailed as a triumph of international environmental advocacy. It occurred as a growing number of conservation-oriented biologists were beginning to argue forcefully for scientifically managed conservation of species and ecosystems – the same scientists who would, by the mid-1980s, call themselves conservation biologists. Although India accepted international funds to implement Project Tiger, it strictly limited research posts to Government of India Foresters, against the protests of Indian and US biologists who hoped to conduct the scientific studies that would lead to better management and thus more effective conservation of the tiger. The foresters were not trained to conduct research, and in fact did not produce any of significance for the first 15 years of Project Tiger’s existence. The failure of biologists to gain access to India’s tigers in the 1970s was caused by many factors, but not least among them was a history of disdain among conservation-oriented biologists for government officials managing reserves, and the local politics of conservation. Project Tiger, then, serves as a case study for the discussion of the intersection of conservation biology with non-scientific concerns, including nationalism and the desire of the Indian government to more completely control its land.¹I would like to thank the participants in the 2003 Southwest Colloquium for the Life Sciences for their constructive comments on an earlier version of this paper, as well as the two unusually helpful (anonymous) reviewers.     

Patterns of recruitment and spawning in Hawaiian reef fishes

Synopsis Recruitment of juvenile fishes to five 25 m² quadrats on an extensive natural reef in Kona, Hawaii was monitored over 51 months. Pronounced between-year variability in recruit abundance was evident for some species. Many exhibited strikingly low levels of recruitment. Overall recruitment was highly seasonal with a major peak in June and July, and a generally smaller, secondary peak in February and March. Recruitment was minimal during early winter (October–December) and a review of other studies similarly indicates minimal recruitment in Hawaii during this period. Spawning in Hawaiian fishes generally begins during the winter months of relatively low temperatures, increases during late winter and early summer and declines rapidly as maximum summer water temperatures are reached (September–October). Seasonal changes in food availability, ocean currents or salinity seem unlikely to be responsible for observed patterns of recruitment and spawning. Rather, the patterns appear to be most closely tied to changes in water temperature or photoperiod. Loss of propagules to offshore-moving eddies or other unfavorable currents may be responsible for the low levels of juvenile recruitment found in this and other Hawaiian studies. In Kona, at least 6 species of fishes recruited in pulses during quarter or new moon phases. Four other species have been reported elsewhere in Hawaii to recruit during either new or full moon phases. Lunar spawning periodicity was present in fewer than half of the species so far examined, and no single adaptive function for lunar periodicity was applicable to all species.     

虎的日粮营养和表观消化率的测定

为了解动物园中圈养虎对日粮中各主要营养成分的摄入量及其表观消化率,于2004年12月对6只华南虎(Panthera tigris amoyensis)和1只孟加拉虎(P.t.tigris)日粮的营养成分进行了分析,并测定了其表观消化率。结果表明,尽管每只虎的日粮组成及其营养成分不尽相同,但是虎对粗蛋白、脂肪等主要营养成分和能量的表观消化率都很高,而且非常接近,分别为(97±0.7)%、(98±1.0)%和(97±1.3)%;对干物质及灰分的表观消化率差异较大,分别为86%~95%,36%~65%,估计与日粮中骨骼成分含量差异较大有关。其中成年虎对粗蛋白、脂肪、能量的每日摄入量分别为:(1 061.3±134.4)g,(251.3±63.3)g,(35 276.7±6 009.1)kJ。     

Influence of lunar phases on suicide: the end of a myth? A population-based study

The hypothesis of lunar influence on suicide remains widespread, despite the fact that little scientific evidence to substantiate it. We conducted a population-based study to assess the influence of the lunar phases on suicides according to age, sex, and chosen method. The study included all suicides in Middle Franconia between 1998 and 2003. From a population-based sample of 3351 events, the files of 3054 suicides (1949 males and 1105 females) were complete for the study variables. Data were categorized by lunar phase, sex, age, and chosen method—“violent” vs. “non-violent” acts. No significant relationship was detected between the full, absent, and moon's interphases and suicide incidence. Nevertheless, there was a weak association between the absent moon and choice of a non-violent suicide method in men aged less than the median of 40.2 yrs. There was no evidence of a relationship between suicide and lunar phase. Some explanations for this phenomenon are discussed.     

Cysteine-rich protein 61 (CCN1) and connective tissue growth factor (CCN2) at the crosshairs of ocular neovascular and fibrovascular disease therapy

Abstract

The vasculature forms a highly branched network investing every organ of vertebrate organisms. The retinal circulation, in particular, is supported by a central retinal artery branching into superficial arteries, which dive into the retina to form a dense network of capillaries in the deeper retinal layers. The function of the retina is highly dependent on the integrity and proper functioning of its vascular network and numerous ocular diseases including diabetic retinopathy, age-related macular degeneration and retinopathy of prematurity are caused by vascular abnormalities culminating in total and sometimes irreversible loss of vision. CCN1 and CCN2 are inducible extracellular matrix (ECM) proteins which play a major role in normal and aberrant formation of blood vessels as their expression is associated with developmental and pathological angiogenesis. Both CCN1 and CCN2 achieve disparate cell-type and context-dependent activities through modulation of the angiogenic and synthetic phenotype of vascular and mesenchymal cells respectively. At the molecular level, CCN1 and CCN2 may control capillary growth and vascular cell differentiation by altering the composition or function of the constitutive ECM proteins, potentiating or interfering with the activity of various ligands and/or their receptors, physically interfering with the ECM-cell surface interconnections, and/or reprogramming gene expression driving cells toward new phenotypes. As such, these proteins emerged as important prognostic markers and potential therapeutic targets in neovascular and fibrovascular diseases of the eye. The purpose of this review is to highlight our current knowledge and understanding of the most recent data linking CCN1 and CCN2 signaling to ocular neovascularization bolstering the potential value of targeting these proteins in a therapeutic context.