Extracellular matrix components associated with remodeling processes in brain

In the central nervous system, various extracellular matrix components have been identified which are strongly expressed during development and in most areas of the brain down-regulated during maturation. Examples are tenascin-C, neurocan and hyaluronan. While tenascin-C is well known to be associated with morphogenic events and the active contribution of hyaluronan to various physiological processes is increasingly acknowledged, neurocan belongs to a class of molecules thought to be generally more associated with barrier functions: chondroitin sulfate proteoglycans. Consideration of these and related molecules and their processing in the context of the general organization of the brain extracellular matrix, their changes during brain maturation and their implication in different types of remodeling processes in adult brain, like normal and pathological synaptic plasticity, inflammatory and dementia-associated diseases and gliomas, may indicate that components of the extracellular matrix could provide valuable early information about the pathological state of the brain.Received 29 January 2004; received after revision 25 March 2004; accepted 2 April 2004     

Neurocan: a brain chondroitin sulfate proteoglycan

Neurocan is a chondroitin sulfate proteoglycan of the lectican family and a component of the extracellular matrix of the central nervous system. It is mainly expressed during modeling and remodeling stages of this tissue. Neurocan can bind to various structural extracellular matrix components, such as hyaluronan, heparin, tenascin-C and tenascin-R, and the growth and mobility factors FGF-2, HB-GAM, and amphoterin. Neurocan can also interact with several cell surface molecules, such as N-CAM, L1/Ng-CAM, TAG-1/axonin-1, and an N-cadherin-binding N-acetyl-galactosamine-phosphoryl-transferase, and in vitro studies have shown that neurocan is able to modulate the cell-binding and neurite outgrowth promoting activites of these molecules. Current analysis of the molecular structures and substructures involved in homophilic and heterophilic interactions of these molecules and complementary loss-of-function mutations might shed some light on the roles played by neurocan and interacting molecules in the fine tuning of the nervous system.     

Pre- and post-natal ontogeny of neutral endopeptidase 24-11 ('enkephalinase') studied by in vitro autoradiography in the rat.

Neutral endopeptidase (NEP, enkephalinase, CALLA) which is present in various neural and non-neural tissues, is able to cleave a variety of regulatory peptides. The distribution of NEP has been studied during rat pre- and post-natal development by autoradiography after in vitro binding of the tritiated inhibitor [3H]HACBO-Gly to whole-body and organ sections. In the central nervous system (CNS), where the presence of NEP has been related to the termination of the action of enkephalins, the external layer of the olfactory bulbs is the only structure prominently labeled before birth. Other CNS structures rich in NEP in the adult, such as the nigrostriatal tract, are progressively labeled after birth. Outside the CNS, the progressive appearance of NEP in the kidney, the lungs and the salivary glands suggests its concomitant involvement in adult physiological functions, including fluid balance control, possibly by cleaving the atrial natriuretic peptide (ANP) and other peptides. On the other hand, transient or enhanced expression of NEP is observed during the development of several organs such as the sensory organs, the heart and the major blood vessels, the intestine, the bones and the genital tubercle. In addition to the still incompletely known physiological functions of the enzyme, the developmental pattern of its expression in several tissues strongly suggests a modulatory role for NEP in the ontogeny of a large number of organs.     

Purinergic signaling in embryonic and stem cell development

Nucleotides are of crucial importance as carriers of energy in all organisms. However, the concept that in addition to their intracellular roles, nucleotides act as extracellular ligands specifically on receptors of the plasma membrane took longer to be accepted. Purinergic signaling exerted by purines and pyrimidines, principally ATP and adenosine, occurs throughout embryologic development in a wide variety of organisms, including amphibians, birds, and mammals. Cellular signaling, mediated by ATP, is present in development at very early stages, e.g., gastrulation of Xenopus and germ layer definition of chick embryo cells. Purinergic receptor expression and functions have been studied in the development of many organs, including the heart, eye, skeletal muscle and the nervous system. In vitro studies with stem cells revealed that purinergic receptors are involved in the processes of proliferation, differentiation, and phenotype determination of differentiated cells. Thus, nucleotides are able to induce various intracellular signaling pathways via crosstalk with other bioactive molecules acting on growth factor and neurotransmitter receptors. Since normal development is disturbed by dysfunction of purinergic signaling in animal models, further studies are needed to elucidate the functions of purinoceptor subtypes in developmental processes.     

Intrinsic and extrinsic neural and neurohumoral control of the decapod heart

The intra-cardiac nervous system of the decapod heart is composed of large and small ganglionic cells (LGCs and SGCs) and axons of extrinsic cardio-acceleratory and-inhibitory neurons (CAs and CIs). Candidate neurotransmitters for the neurons have been determined by pharmacological, cytochemical and immunocytochemical tests. SGCs may be cholinergic, LGCs and CAs are probably dopaminergic, and CIs are GABAergic. Serotonin and octopamine were cardio-excitatory neuromodulators of the heart. Proctolin, crustacean cardio-active peptide (CCAP), red pigment concentrating hormone (RPCH), and FMRFamide also had modulatory actions on the heart. Proctolin was the most potent peptide, which acted primary on the cardiac ganglion. Insect adipokinetic hormones had little effect on the heart.     

Functional aspects of animal microRNAs

MicroRNAs (miRNAs) are a recently discovered family of small regulatory molecules that function by modulating protein production. There are approximately 500 known mammalian miRNA genes, and each miRNA may regulate hundreds of different protein-coding genes. Mature miRNAs bind to target mRNAs in a protein complex known as the miRNA-induced silencing complex (miRISC), sometimes referred to as the miRNP (miRNA-containing ribonucleoprotein particles), where mRNA translation is inhibited or mRNA is degraded. These actions of miRNAs have been shown to regulate several developmental and physiological processes including stem cell differentiation, haematopoiesis, cardiac and skeletal muscle development, neurogenesis, insulin secretion, cholesterol metabolism and the immune response. Furthermore, aberrant expression has been implicated in a number of diseases including cancer and heart disease. The role of miRNAs in these developmental, physiological and pathological processes will be reviewed. Received 3 August 2007; received after revision 3 October 2007; accepted 5 October 2007     

Pre-and post-natal ontogeny of neutral endopeptidase 24-11 (‘enkephalinase’) studied by in vitro autoradiography in the rat

Neutral endopeptidase (NEP, enkephalinase, CALLA) which is present in various neural and non-neural tissues, is able to cleave a variety of regulatory peptides. The distribution of NEP has been studied during rat pre-and post-natal development by autoradiography after in vitro binding of the tritiated inhibitor [³H]HACBO-Gly to whole-body and organ sections. In the central nervous system (CNS), where the presence of NEP has been related to the termination of the action of enkephalins, the external layer of the olfactory bulbs is the only structure prominently labeled before birth. Other CNS structures rich in NEP in the adult, such as the nigrostriatal tract, are progressively labeled after birth. Outside the CNS, the progressive appearance of NEP in the kidney, the lungs and the salivary glands suggests its concomitant involvement in adult physiological functions, including fluid balance control, possibly by cleaving the atrial natriuretic peptide (ANP) and other peptides. On the other hand, transient or enhanced expression of NEP is observed during the development of several organs such as the sensory organs, the heart and the major blood vessels, the intestine, the bones and the genital tubercle. In addition to the still incompletely known physiological functions of the enzyme, the developmental pattern of its expression in several tissues strongly suggests a modulatory role for NEP in the ontogeny of a large number of organs.     

The neurotrophic factors in non-neuronal tissues

Although neurotrophic factors are defined as molecules that maintain neuronal cells, they possess a range of functions outside the nervous system. For example, glial cell line-derived neurotrophic factor is essential for ureteric branching in kidney morphogenesis and for regulating the fate of stem cells during spermatogenesis. Leukemia inhibitory factor, a member of the interleukin-6 (IL-6) ciliary neurotrophic factor family, inhibits differentiation of embryonic stem cells, induces tubulogenesis in the embryonic kidney, and regulates sperm differentiation. Other IL-6 family members are important in cardiac differentiation and they have pleiotropic functions in the hematopoietic and immune systems. Although neurotrophin receptors have been found on a number of non-neuronal tissues, they represent mostly truncated receptor isoforms that are incapable of signal transduction and may have scavenger or dominant negative functions. However, several examples can be presented of essential non-neuronal functions played by neurotrophins in e.g., cardiac, hair follicle, and vascular differentiation, and the maintenance of immune cells.     

Melanocortin receptors: their functions and regulation by physiological agonists and antagonists

The melanocortins are a family of bioactive peptides derived from proopiomelanocortin, and share significant structural similarity. Those peptides are best known for their stimulatory effects on pigmentation and steroidogenesis. Melanocortins are synthesized in various sites in the central nervous system and in peripheral tissues, and participate in regulating multiple physiological functions. Research during the past decade has provided evidence that melanocortins elicit their diverse biological effects by binding to a distinct family of G protein-coupled receptors with seven transmembrane domains. To date, five melanocortin receptor genes have been cloned and characterized. Those receptors differ in their tissue distribution and in their ability to recognize the various melanocortins and the physiological antagonists, agouti signaling protein and agouti-related protein. These advances have opened new horizons for exploring the significance of melanocortins, their antagonists, and their receptors in a variety of important physiological functions. Received 5 October 2000; accepted 10 November 2000     

Peptides in the mammalian cardiovascular system

Summary Ample immunocytochemical evidence is now available demonstrating that several peptides are present in the mammalian cardiovascular system where they are localised to nerve fibres and myocardial cells. The neuropeptides (neuropeptide Y, calcitonin gene-related peptide, tachykinins and vasoctive intestinal polypeptide) are localised to large secretory vesicles in subpopulations of afferent or efferent nerves supplying the heart and vasculature of several mammals, including man. Although they often exert potent pharmacological effects on the tissues in which they occur their physiological significance has still to be established. They may act directly via specific receptors and/or indirectly by influencing the release and action of other cardiovascular transmitters. In marked contrast, atrial natriuretic peptide is produced by cardiac myocytes and considered to act as a circulating hormone.     

Peptides in the mammalian cardiovascular system

Ample immunocytochemical evidence is now available demonstrating that several peptides are present in the mammalian cardiovascular system where they are localised to nerve fibres and myocardial cells. The neuropeptides (neuropeptide Y, calcitonin gene-related peptide, tachykinins and vasoactive intestinal polypeptide) are localised to large secretory vesicles in subpopulations of afferent or efferent nerves supplying the heart and vasculature of several mammals, including man. Although they often exert potent pharmacological effects on the tissues in which they occur their physiological significance has still to be established. They may act directly via specific receptors and/or indirectly by influencing the release and action of other cardiovascular transmitters. In marked contrast, atrial natriuretic peptide is produced by cardiac myocytes and considered to act as a circulating hormone.     

Cardiac and circulatory control in decapod Crustacea with comparisons to molluscs

Summary In this review I will attempt to identify the circulatory requirements a decapod is likely to encounter and how the heart is controlled to meet these demands. The decapod heart has been designed as an autonomous system endowed with an intrinsic autorhythmic pacemaker ganglion. Muscle fibers are multiply-innervated and capable of producing regenerative action potentials. This vitally important organ has been designed to be nearly fail-safe. Stroke volume is more important than heart rate in determining cardiac output. Stretch sensitivity of the cardiac ganglion and of the myocardium as well as extrinsic nervous and hormonal modulation of the heart can all contribute to changes in stroke volume. It may be advantageous to an animal to switch the circulation between various vascular beds to meet changing perfusion demands. Neuronal and hormonal mechanisms have been identified which exert differential control of the cardioarterial valves, but it is not known whether switching does occur and if so whether these valves participate in the process. Changes in peripheral resistance can also redirect circulatory flow. The circulatory and ventilatory systems demonstrate coordinated rate changes which suggest that the heart is responding to meet changing ventilatory performance requirements. This coupling is controlled both by the hydrostatic pressure pulses generated within the branchial chambers and by common higher level nervous inputs. Comparisons of the cardiovascular systems of crustaceans and molluscs, based on the papers presented at this symposium, are high-lighted.     

The relative distribution of soluble and insoluble cholinesterases in rat excitable tissues

Summary Three ratios were studied here: bound to free AChE (R₁), bound to free BChE (R₂), and the ratios between these two (R₃). The first one proved relevant in that it contributed to the division of the cholinergic tissues into 3 classes: high values (nicotinic tissues: skeletal muscle), low values(muscarinic tissues: small intestine, uterus, heart), and middle values (mixed, nicotinic and muscarinic cholinergic innervation:brain). The third ratio (R₃) showed different values in the muscarinic tissues studied; no significant differences could, however, be found between the ratios of brain and skeletal muscle. Further exploration of this ratio should indicate whether it is of some importance for the characterization of excitable tissues.     

Neurexins and neuroligins: synapses look out of the nervous system

The scientific interest in the family of the so-called nervous vascular parallels has been growing steadily for the past 15 years, either by addition of new members to the group or, lately, by deepening the analysis of established concepts and mediators. Proteins governing both neurons and vascular cells are known to be involved in events such as cell fate determination and migration/guidance but not in the last and apparently most complex step of nervous system development, the formation and maturation of synapses. Hence, the recent addition to this family of the specific synaptic proteins, Neurexin and Neuroligin, is a double innovation. The two proteins, which were thought to be “simple” adhesive links between the pre- and post-synaptic sides of chemical synapses, are in fact extremely complex and modulate the most subtle synaptic activities. We will discuss the relevant data and the intriguing challenge of transferring synaptic activities to vascular functions.     

The many faces of semaphorins: from development to pathology

The semaphorin family is a large group of proteins controlling cell migration and axonal growth cone guidance. These proteins are bi-functional signals capable of growth promotion or growth inhibition. Initially described in the nervous system, the majority of studies related to semaphorins and semaphorin signalling are nowadays performed in model systems outside the nervous system. Here, we provide an exhaustive review of the many faces of semaphorins both during developmental, regulatory and pathological processes. Indeed, because of their crucial fundamental roles, the semaphorins and their receptors represent important targets for the development of drugs directed at a variety of diseases. Received 22 August 2008; received after revision 22 September 2008; accepted 24 September 2008 L. Roth, E. Koncina, S. Satkauskas: These authors contributed equally to this work.     

Expression of nerve growth factor-like polypeptides and immunoreactivity related to the two types of neurotrophin receptors in earthworm tissues

Nerve growth factor (NGF) belongs by sequence homology to the neurotrophins, a family of proteins binding the same p75 receptor and closely related members of the Trk family of receptor tyrosine kinases. Fundamental in the vertebrate nervous system, neurotrophin signals have also been suggested as essential for relatively complex nervous systems occurring in invertebrate species that live longer than Caenorhabditis elegans and Drosophila melanogaster. Mammalian neurotrophins have been found to influence invertebrate neuronal growth. However, there are only a few data on the presence of molecules related to neurotrophin signalling components in invertebrates. Our studies provide evidence that analogues of neurotrophins and neurotrophin receptors are expressed in Eisenia foetida earthworms. In particular, NGF-like and Trk-like immunoreactive proteins are both expressed in the nervous system, whereas p75-like positivity identifies tubular structures associated with dorsal pores that are involved in the earthworm response to mechanical irritation or stress. Received 12 November 2001; received after revision 8 January 2002; accepted 8 January 2002     

Periostin and its interacting proteins in the construction of extracellular architectures

Periostin is a matricellular protein that is composed of a multi-domain structure with an amino-terminal EMI domain, a tandem repeat of four FAS 1 domains, and a carboxyl-terminal domain. These distinct domains have been demonstrated to bind to many proteins including extracellular matrix proteins (Collagen type I and V, fibronectin, tenascin, and laminin), matricellular proteins (CCN3 and βig-h3), and enzymes that catalyze covalent crosslinking between extracellular matrix proteins (lysyl oxidase and BMP-1). Adjacent binding sites on periostin have been suggested to put the interacting proteins in close proximity, promoting intermolecular interactions between each protein, and leading to their assembly into extracellular architectures. These extracellular architectures determine the mechanochemical properties of connective tissues, in which periostin plays an important role in physiological homeostasis and disease progression. In this review, we introduce the proteins that interact with periostin, and discuss how the multi-domain structure of periostin functions as a scaffold for the assembly of interacting proteins, and how it underlies construction of highly sophisticated extracellular architectures.     

The admiR-able advances in cardiovascular biology through the zebrafish model system

MicroRNAs are small non-coding RNAs endogenously expressed by all tissues during development and adulthood. They regulate gene expression by controlling the stability of targeted messenger RNA. In cardiovascular tissues microRNAs play a role by modulating essential genes involved in heart and blood vessel development and homeostasis. The zebrafish (Danio rerio) system is a recognized vertebrate model system useful to study cardiovascular biology; recently, it has been used to investigate microRNA functions during natural and pathological states. In this review, we will illustrate the advantages of the zebrafish model in the study of microRNAs in heart and vascular cells, providing an update on recent discoveries using the zebrafish to identify new microRNAs and their targeted genes in cardiovascular tissues. Lastly, we will provide evidence that the zebrafish is an optimal model system to undercover new microRNA functions in vertebrates and to improve microRNA-based therapeutic approaches.