Interpretation of the gingival inflammatory infiltrate]

The investigation of tooth eruption in dermoid cysts of the ovary allows one to observe in the chorion at the level of the epithelial attachment, an anatomical component that seems to correspond to a local system of defense. Up until now this has been considered to be a secondary inflammatory response resulting from the bacterial or mechanical assault. This component is found to form when the tooth erupts and constitutes an important element in the physico-pathogical process and of the immune response of the dental organ.     

Amelogenin gene splice products: potential signaling molecules

The amelogenins, the major proteins of the developing tooth enamel matrix, are highly conserved throughout most species studied. The gene structure is similar, with a set of seven exons and intervening introns, and remarkable conservation of particular exon sizes over divergent species. Studies of exon skipping and consequent alternative gene splicing suggest that, in vertebrates, exon definition is crucial. In this mechanism, exon size is important. If too small, an exon can be readily skipped, if too large, internal cryptic splice sites may be utilized. Other factors, such as intron length and specific nucleotide sequences at the splice boundaries also modulate splicing efficiency, but amelogenin gene splicing conforms well to the generalized exon length model. Exons 1, 2 and 7 are not subject to splicing that affects the secreted protein product, but exons 3, 4 and 5 are at the lower boundary of exon size, rendering them, 4 and 5 especially, subject to skipping. On the other hand, exon 6 is very long and has cryptic splicing sites that can be used. In the mouse, nine distinct splice product proteins have been detected. The question now is the functions of these products. The larger forms, those that contain the intact proline-rich, hydrophobic exon 6 domains, are important for enamel mineralization. Recent work suggests that the small proteins resulting from deletion of a major part of amelogenin gene exon 6 via utilization of a cryptic site may have signal transduction functions during tooth development. Furthermore, new work also suggests that odontoblasts transiently express the small amelogenins during the period that epithelial-mesenchymal signaling between preodontoblasts and preameloblasts determines the course of tooth development. The same peptides have been demonstrated to act on non-odontogenic cells and effect their phenotypic expression patterns in vitro, and to induce bone formation in implants in vivo. Received 20 March 2002; received after revision 2 July 2002; accepted 3 July 2002     

Roles of innervation in developing and regenerating orofacial tissues

The head is innervated by 12 cranial nerves (I–XII) that regulate its sensory and motor functions. Cranial nerves are composed of sensory, motor, or mixed neuronal populations. Sensory neurons perceive generally somatic sensations such as pressure, pain, and temperature. These neurons are also involved in smell, vision, taste, and hearing. Motor neurons ensure the motility of all muscles and glands. Innervation plays an essential role in the development of the various orofacial structures during embryogenesis. Hypoplastic cranial nerves often lead to abnormal development of their target organs and tissues. For example, Möbius syndrome is a congenital disease characterized by defective innervation (i.e., abducens (VI) and facial (VII) nerves), deafness, tooth anomalies, and cleft palate. Hence, it is obvious that the peripheral nervous system is needed for both development and function of orofacial structures. Nerves have a limited capacity to regenerate. However, neural stem cells, which could be used as sources for neural tissue maintenance and repair, have been found in adult neuronal tissues. Similarly, various adult stem cell populations have been isolated from almost all organs of the human body. Stem cells are tightly regulated by their microenvironment, the stem cell niche. Deregulation of adult stem cell behavior results in the development of pathologies such as tumor formation or early tissue senescence. It is thus essential to understand the factors that regulate the functions and maintenance of stem cells. Yet, the potential importance of innervation in the regulation of stem cells and/or their niches in most organs and tissues is largely unexplored. This review focuses on the potential role of innervation in the development and homeostasis of orofacial structures and discusses its possible association with stem cell populations during tissue repair.     

Kallikrein-related peptidases

Kallikrein 1 (KLK1), a key component of the kallikrein-kinin system, originates from a locus on the long arm of chromosome 19 that contains several related serine endopeptidases. The biological role of these kallikrein-related peptidases is not clear, but emerging evidence suggests that they might be important in several physiological systems, e.g., in male reproduction, skin homeostasis, tooth enamel formation and neural development and plasticity. The kallikrein locus has undergone some major evolutionary events. Most spectacular are relatively recent duplications of KLK1 that have created 13 and 9 functional genes that are unique to the mouse and the rat, respectively. Human paralogs are KLK2 and KLK3: the latter encoding the cancer biomarker prostate-specific antigen. In this review on kallikrein-related peptidases, the focus is on their evolution, their role in skin homeostasis and semen liquefaction, and their utility as cancer biomarkers.     

Iron deposits in the chronically inflamed central nervous system and contributes to neurodegeneration

Neurodegenerative disorders are characterized by the presence of inflammation in areas with neuronal cell death and a regional increase in iron that exceeds what occurs during normal aging. The inflammatory process accompanying the neuronal degeneration involves glial cells of the central nervous system (CNS) and monocytes of the circulation that migrate into the CNS while transforming into phagocytic macrophages. This review outlines the possible mechanisms responsible for deposition of iron in neurodegenerative disorders with a main emphasis on how iron-containing monocytes may migrate into the CNS, transform into macrophages, and die out subsequently to their phagocytosis of damaged and dying neuronal cells. The dying macrophages may in turn release their iron, which enters the pool of labile iron to catalytically promote formation of free-radical-mediated stress and oxidative damage to adjacent cells, including neurons. Healthy neurons may also chronically acquire iron from the extracellular space as another principle mechanism for oxidative stress-mediated damage. Pharmacological handling of monocyte migration into the CNS combined with chelators that neutralize the effects of extracellular iron occurring due to the release from dying macrophages as well as intraneuronal chelation may denote good possibilities for reducing the deleterious consequences of iron deposition in the CNS.     

Molecular and engineering approaches to regenerate and repair teeth in mammals

Continuous replacement of teeth throughout the lifespan of an individual is possibly basal for most of the vertebrates including fish and reptiles; however, mammals generally have a limited capacity of tooth renewal. The ability to induce cellular differentiation in adults to replace lost or damaged cells in mammals, or to tissue-engineer organs in vitro, has hence become one of the major goals of regenerative medicine. In this article, we will revisit some of the important signals and tissue interactions that regulate mammalian tooth development, and will offer a synopsis of the latest progress in tooth regeneration and repair via molecular and engineering approaches. It is hoped that this article will not only offer an overview of recent technologies in tooth regeneration and repair but will also stimulate more interdisciplinary research in this field to turn the pursuit of tooth regeneration and repair into practical reality.     

The multifaceted role of periostin in tumorigenesis

Periostin, also called osteoblast-specific factor 2 (OSF-2), is a member of the fasciclin family and a disulfide-linked cell adhesion protein that has been shown to be expressed preferentially in the periosteum and periodontal ligaments, where it acts as a critical regulator of bone and tooth formation and maintenance. Furthermore, periostin plays an important role in cardiac development. Recent clinical evidence has also revealed that periostin is involved in the development of various tumors, such as breast, lung, colon, pancreatic, and ovarian cancers. Periostin interacts with multiple cell-surface receptors, most notably integrins, and signals mainly via the PI3-K/Akt and other pathways to promote cancer cell survival, epithelial–mesenchymal transition (EMT), invasion, and metastasis. In this review, aspects related to the function of periostin in tumorigenesis are summarized.     

Regulation and dysregulation of astrocyte activation and implications in tumor formation

Astrocytic activation is a cellular response to disturbances of the central nervous system (CNS). Recent advances in cellular and molecular biology have demonstrated the remarkable changes in molecular signaling, morphology, and metabolism that occur during astrocyte activation. Based on these studies, it has become clear that the astrocyte activation process is regulated by a variety of signaling pathways, which result in metabolic support, wound healing and scar formation. While normal astrocyte activation pathways drive homeostasis and/or repair in the CNS, dysregulation of these pathways can lead to astrocyte abnormalities, including glioma formation with similar phenotypes as reactive astrocytes. We review the principle pathways responsible for astrocytic activation, as well as their potential contribution to tumor formation in the CNS.     

The role of the insulin-like growth factor (IGF) axis in osteogenic and odontogenic differentiation

The insulin-like growth factor (IGF) axis is a multicomponent molecular network which has important biological functions in the development and maintenance of differentiated tissue function(s). One of the most important functions of the IGF axis is the control of skeletal tissue metabolism by the finely tuned regulation of the process of osteogenesis. To achieve this, the IGF axis controls the activity of several cell types—osteoprogenitor cells, osteoblasts, osteocytes and osteoclasts to achieve the co-ordinated development of appropriate hard tissue structure and associated matrix deposition. In addition, there is an increasing awareness that the IGF axis also plays a role in the process of odontogenesis (tooth formation). In this review, we highlight some of the key findings in both of these areas. A further understanding of the role of the IGF axis in hard tissue biology may contribute to tissue regeneration strategies in cases of skeletal tissue trauma.     

Antimicrobial and antiviral activity of xylosyl-methylthio-adenosine, a naturally occurring analogue of methylthio-adenosine from Doris verrucosa.

Xylosyl-methylthio-adenosine, a naturally occurring analogue of 5'-deoxy-5'-methylthio-adenosine, has been postulated to play a protective role during egg development in the mollusc Doris verrucosa. However, in vitro tests showed that this analogue is devoid of activity against fungi, bacteria and viruses.     

Mechanisms controlling germline cyst breakdown and primordial follicle formation

In fetal females, oogonia proliferate immediately after sex determination. The progress of mitosis in oogonia proceeds so rapidly that the incompletely divided cytoplasm of the sister cells forms cysts. The oogonia will then initiate meiosis and arrest at the diplotene stage of meiosis I, becoming oocytes. Within each germline cyst, oocytes with Balbiani bodies will survive after cyst breakdown (CBD). After CBD, each oocyte is enclosed by pre-granulosa cells to form a primordial follicle (PF). Notably, the PF pool formed perinatally will be the sole lifelong oocyte source of a female. Thus, elucidating the mechanisms of CBD and PF formation is not only meaningful for solving mysteries related to ovarian development but also contributes to the preservation of reproduction. However, the mechanisms that regulate these phenomena are largely unknown. This review summarizes the progress of cellular and molecular research on these processes in mice and humans.     

Antimicrobial and antiviral activity of xylosyl-methylthio-adenosine,a naturally occurring analogue of methylthio-adenosine fromDoris verrucosa

Xylosyl-methylthio-adenosine, a naturally occurring analogue of 5′-deoxy-5′-methylthio-adenosine, has been postulated to play a protective role during egg development in the molluscDoris verrucosa. However, in vitro tests showed that this analogue is devoid of activity against fungi, bacteria and viruses.     

Fetal rat brain hemisphere tissue in nonadherent stationary organ culture

A simple organ culture system for brain tissue is described. Fragments of fetal rat brain hemisphere tissue are explanted to multiwell dishes base-coated with semisolid agar. In this system nonadherent organ culture can be performed for at least 50 days. Cell migration, biochemical and morphological differentiation and the formation of a layered architecture seem to mimic some of the phenomena occurring in the developing rat brain in vivo. The fragments may therefore be a useful organ culture model for nervous tissue.     

Fetal rat brain hemisphere tissue in nonadherent stationary organ culture

Summary A simple organ culture system for brain tissue is described. Fragments of fetal rat brain hemisphere tissue are explanted to multiwell dishes base-coated with semisolid agar. In this system nonadherent organ culture can be performed for at least 50 days. Cell migration, biochemical and morphological differentiation and the formation of a layered architecture seem to mimic some of the phenomena occurring in the developing rat brain in vivo. The fragments may therefore be a useful organ culture model for nervous tissue.     

Filamentous actin accumulates during plant cell penetration and cell wall plug formation in <Emphasis Type="Italic">Phytophthora infestans</Emphasis>

The oomycete Phytophthora infestans is the cause of late blight in potato and tomato. It is a devastating pathogen and there is an urgent need to design alternative strategies to control the disease. To find novel potential drug targets, we used Lifeact-eGFP expressing P. infestans for high resolution live cell imaging of the actin cytoskeleton in various developmental stages. Previously, we identified actin plaques as structures that are unique for oomycetes. Here we describe two additional novel actin configurations; one associated with plug deposition in germ tubes and the other with appressoria, infection structures formed prior to host cell penetration. Plugs are composed of cell wall material that is deposited in hyphae emerging from cysts to seal off the cytoplasm-depleted base after cytoplasm retraction towards the growing tip. Preceding plug formation there was a typical local actin accumulation and during plug deposition actin remained associated with the leading edge. In appressoria, formed either on an artificial surface or upon contact with plant cells, we observed a novel aster-like actin configuration that was localized at the contact point with the surface. Our findings strongly suggest a role for the actin cytoskeleton in plug formation and plant cell penetration.     

Neurotrophins and neuronal differentiation in the central nervous system

The central nervous system requires the proper formation of exquisitely precise circuits to function properly. These neuronal circuits are assembled during development by the formation of synaptic connections between hundreds of thousands of differentiating neurons. For these circuits to form correctly, neurons must elaborate precisely patterned axonal and dendritic arbors. Although the cellular and molecular mechanisms that guide neuronal differentiation and formation of connections remain mostly unknown, the neurotrophins have emerged recently as attractive candidates for regulating neuronal differentiation in the developing brain. The experiments reviewed here provide strong support for a bifunctional role for the neurotrophins in axonal and dendritic growth and are consistent with the exciting possibility that the neurotrophins might mediate activity-dependent synaptic plasticity.     

Endogenous retroviruses

Sheep betaretroviruses offer a unique model system to study the complex interaction between retroviruses and their host. Jaagsiekte sheep retrovirus (JSRV) is a pathogenic exogenous retrovirus and the causative agent of ovine pulmonary adenocarcinoma. The sheep genome contains at least 27 copies of endogenous retroviruses (enJSRVs) highly related to JSRV. enJSRVs have played several roles in the evolution of the domestic sheep as they are able to block the JSRV replication cycle and play a critical role in sheep conceptus development and placental morphogenesis. Available data strongly suggest that some dominant negative enJSRV proviruses (i.e. able to block JSRV replication) have been positively selected during evolution. Interestingly, viruses escaping the transdominant enJSRV loci have recently emerged (less than 200 years ago). Thus, endogenization of these retroviruses may still be occurring today. Therefore, sheep provide an exciting and unique system to study retrovirus-host coevolution. (Part of a Multi-author Review)     

Heat shock protein gene expression during embryonic development of the zebrafish

Heat shock genes exhibit complex patterns of spatial and temporal regulation during embryonic development of a wide range of organisms. Our laboratory has been involved in an analysis of heat shock gene expression in the zebrafish, a model system which is now utilized extensively for the examination of early embryonic development of vertebrates. Members of the zebrafish hsp47, hsp70 and hsp90 gene families have been cloned and shown to be closely related to their counterparts in higher vertebrates. Expression of these genes has been examined using Northern blot and whole mount in situ hybridization analyses. Both the hsp47 and hsp90 genes are expressed in a highly tissue-restricted manner during normal development. The data raise a number of interesting questions regarding the function and regulation of these heat shock genes during early zebrafish development.