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Nerve growth factor (NGF) was localized in the submandibular gland of adult male mice by a direct immunocytochemical method using highly purified antibodies against NGF coupled to horseradish peroxidase. In light microscopic sections the reaction product was entirely confined to the cells of the secretory tubules. The acinar part of the gland was free of reaction product. This finding was confirmed by electron microscopy. Within the cells NGF was localized exclusively in the apical secretory granules. No reaction was observed in the rough endoplasmic reticulum, the Golgi region or in the granules of the basal part of the cells. This observation favours the assumption that NGF is derived from a precursor molecule and that the precursor is transformed into immunologically active NGF within the secretory granules during their transport from the basal to the apical part of the tubular cells. Stimulation of the submandibular gland with carbachol (2 mg/kg) led to a massive release of the content of the secretory granules, including NGF, into the salivary duct. [ABSTRACT FROM AUTHOR]

Klaus and his team's results strongly suggest that motoneurons and also sensory neurons that are expressing either GDF15 receptor GFRAL or GDF15 can bind to and signal via an alternative, still unknown receptor. Graph Klaus Unsicker published first studies on growth factors investigating the effects of nerve growth factor (NGF) on adrenal chromaffin cells in 1977-1978 (Unsicker et al. [13], [14]). They bind to ligand specificity determining GDNF family receptor alpha (GFR ) proteins and signal to the cells via transmembrane receptor tyrosine kinase RET. [Extracted from the article]

Brain-derived neurotrophic factor (BDNF) is known to control a wide variety of brain functions, ranging from memory formation to food intake. However, since the BDNF levels are extremely low in the nervous system, the dynamics in neurons from intracellular trafficking to secretion is absolutely complicated; the understanding is not fully promoted. We here review the findings of those critical mechanisms from intracellular trafficking to the secretion of BDNF. Furthermore, to solve this issue, technological advances for the detection, measurement, and imaging of this growth factor are essential. We believe that this review helps the study of these complex but critical mechanisms of BDNF. [ABSTRACT FROM AUTHOR]

The amygdala is a central hub for fear learning assessed by Pavlovian fear conditioning. Indeed, the prevailing hypothesis that learning and memory are mediated by changes in synaptic strength was shown most convincingly at thalamic and cortical afferents to the lateral amygdala. The neurotrophin brain-derived neurotrophic factor (BDNF) is known to regulate synaptic plasticity and memory formation in many areas of the mammalian brain including the amygdala, where BDNF signalling via tropomyosin-related kinase B (TrkB) receptors is prominently involved in fear learning. This review updates the current understanding of BDNF/TrkB signalling in the amygdala related to fear learning and extinction. In addition, actions of proBDNF/p75NTR and NGF/TrkA as well as NT-3/TrkC signalling in the amygdala are introduced. [ABSTRACT FROM AUTHOR]

The neurotrophic factor BDNF is an important regulator for the development of brain circuits, for synaptic and neuronal network plasticity, as well as for neuroregeneration and neuroprotection. Up- and downregulations of BDNF levels in human blood and tissue are associated with, e.g., neurodegenerative, neurological, or even cardiovascular diseases. The changes in BDNF concentration are caused by altered dynamics in BDNF expression and release. To understand the relevance of major variations of BDNF levels, detailed knowledge regarding physiological and pathophysiological stimuli affecting intra- and extracellular BDNF concentration is important. Most work addressing the molecular and cellular regulation of BDNF expression and release have been performed in neuronal preparations. Therefore, this review will summarize the stimuli inducing release of BDNF, as well as molecular mechanisms regulating the efficacy of BDNF release, with a focus on cells originating from the brain. Further, we will discuss the current knowledge about the distinct stimuli eliciting regulated release of BDNF under physiological conditions. [ABSTRACT FROM AUTHOR]

Dendritic spines are tiny membrane specialization forming the postsynaptic part of most excitatory synapses. They have been suggested to play a crucial role in regulating synaptic transmission during development and in adult learning processes. Changes in their number, size, and shape are correlated with processes of structural synaptic plasticity and learning and memory and also with neurodegenerative diseases, when spines are lost. Thus, their alterations can correlate with neuronal homeostasis, but also with dysfunction in several neurological disorders characterized by cognitive impairment. Therefore, it is important to understand how different stages in the life of a dendritic spine, including formation, maturation, and plasticity, are strictly regulated. In this context, brain-derived neurotrophic factor (BDNF), belonging to the NGF-neurotrophin family, is among the most intensively investigated molecule. This review would like to report the current knowledge regarding the role of BDNF in regulating dendritic spine number, structure, and plasticity concentrating especially on its signaling via its two often functionally antagonistic receptors, TrkB and p75NTR. In addition, we point out a series of open points in which, while the role of BDNF signaling is extremely likely conclusive, evidence is still missing. [ABSTRACT FROM AUTHOR]

Neurotrophin signaling via receptor tyrosine kinases is essential for the development and function of the nervous system in vertebrates. TrkB activation and signaling show substantial differences to other receptor tyrosine kinases of the Trk family that mediate the responses to nerve growth factor and neurotrophin-3. Growing evidence suggests that TrkB cell surface expression is highly regulated and determines the sensitivity of neurons to brain-derived neurotrophic factor (BDNF). This translocation of TrkB depends on co-factors and modulators of cAMP levels, N-glycosylation, and receptor transactivation. This process can occur in very short time periods and the resulting rapid modulation of target cell sensitivity to BDNF could represent a mechanism for fine-tuning of synaptic plasticity and communication in complex neuronal networks. This review focuses on those modulatory mechanisms in neurons that regulate responsiveness to BDNF via control of TrkB surface expression. [ABSTRACT FROM AUTHOR]

Most growth factors are synthesized as precursors and biologically active forms are generated by proteolytic cleavage of the pro-domain. However, the biological functions of pro-domains are ill-defined. New roles were recently reported for the pro-domain of brain-derived neurotrophic factor (BDNF), a well-known growth factor in the brain. Interestingly, the pro-domain of BDNF (BDNF pro-peptide) is localized at presynaptic termini, where it facilitates long-term depression (LTD) in hippocampal slices, implicating it as a novel synaptic modulator. BDNF binds its pro-peptide with high affinity in a pH-dependent manner and when bound to BDNF, the BDNF pro-peptide cannot facilitate hippocampal LTD, representing a new mechanism of regulation. The BDNF pro-peptide is present in human cerebrospinal fluid (CSF) and levels were significantly lower in patients with major depressive disorder (MDD) than in controls. Notably, male MDD patients exhibit significantly lower levels of CSF pro-peptide than females. These findings demonstrate that the BDNF pro-peptide is a biologically important synaptic modulator and is associated with MDD, particularly in males. [ABSTRACT FROM AUTHOR]

The role of brain-derived neurotrophic factor (BDNF) and its receptor TrkB has been studied in the context of mood disorders and their treatments for a couple of decades. Pharmacologically diverse antidepressant drugs increase the synthesis of BDNF in the cortex (and some subcortical structures) and this effect accounts for their ability to facilitate neurotrophic processes eventually leading into heightened plasticity within the cortex. Induction of BDNF-TrkB signaling has also been associated with the mechanism of action of ketamine and more recently with some other anesthetics, even with ones not thought to possess antidepressant potential. Notably, both ketamine and conventional antidepressants activate TrkB receptor and its downstream signaling rapidly within the same time scale in the brain while electroconvulsive therapy (ECT), among the most potent inducers of BDNF, has not been unequivocally shown to produce such acute effects on TrkB. The ability of antidepressants to regulate TrkB signaling is developmentally regulated and requires an intact central nervous system. The purpose of this review is to highlight and discuss some of these peculiarities associated with the effects of ketamine and classical antidepressants and BDNF on TrkB signaling. [ABSTRACT FROM AUTHOR]

The sympathetic division of the autonomic nervous system includes a variety of cells including neurons, endocrine cells and glial cells. A recent study (Furlan et al. 2017) has revised thinking about the developmental origin of these cells. It now appears that sympathetic neurons and chromaffin cells of the adrenal medulla do not have an immediate common ancestor in the form a “sympathoadrenal cell”, as has been long believed. Instead, chromaffin cells arise from Schwann cell precursors. This review integrates the new findings with the expanding body of knowledge on the signalling pathways and transcription factors that regulate the origin of cells of the sympathetic division of the autonomic nervous system. [ABSTRACT FROM AUTHOR]

The neural-crest-derived sympathoadrenal cell lineage gives rise to sympathetic neurons and to endocrine chromaffin cells of the adrenal medulla. Both cell types express a largely overlapping set of genes, including those coding for the molecular machinery related to the synthesis and exocytotic release of catecholamines. During their early development, sympathetic neurons and chromaffin cells rely on a shared transcription factor network that controls the establishment of these common features. Despite many similarities, mature sympathetic neurons and chromaffin cells significantly differ regarding their morphology and function. Most prominently, sympathetic neurons possess axons that are absent in mammalian adrenal chromaffin cells. The molecular mechanism underlying the divergent development of sympathoadrenal cells into neuronal and endocrine cells remains elusive. Mutational inactivation of the ribonuclease dicer hints at the importance of microRNAs in this diversification. We show here that miR-124 is detectable in developing sympathetic neurons but absent in chromaffin cell precursors. We further demonstrate that miR-124 promotes neurite elongation when transfected into cultured chromaffin cells indicating its capability to support the establishment of a neuronal morphology in non-neuronal sympathoadrenal cells. Our results also show that treatment of PC12 cells with the neurotrophin nerve growth factor leads to an upregulation of miR-124 expression and that inhibition of miR-124 reduces nerve-growth-factor-induced neurite outgrowth in PC12 cells. Thus, our data indicate that miR-124 contributes to the establishment of specific neuronal features in developing sympathoadrenal cells. [ABSTRACT FROM AUTHOR]

Chromogranin A (CgA) is a prohormone and granulogenic factor in neuroendocrine tissues with a regulated secretory pathway. The impact of CgA depletion on secretory granule formation has been previously demonstrated in cell culture. However, studies linking the structural effects of CgA deficiency with secretory performance and cell metabolism in the adrenomedullary chromaffin cells in vivo have not previously been reported. Adrenomedullary content of the secreted adrenal catecholamines norepinephrine (NE) and epinephrine (EPI) was decreased 30-40 % in Chga-KO mice. Quantification of NE and EPI-storing dense core (DC) vesicles (DCV) revealed decreased DCV numbers in chromaffin cells in Chga-KO mice. For both cell types, the DCV diameter in Chga-KO mice was less (100-200 nm) than in WT mice (200-350 nm). The volume density of the vesicle and vesicle number was also lower in Chga-KO mice. Chga-KO mice showed an ~47 % increase in DCV/DC ratio, implying vesicle swelling due to increased osmotically active free catecholamines. Upon challenge with 2 U/kg insulin, there was a diminution in adrenomedullary EPI, no change in NE and a very large increase in the EPI and NE precursor dopamine (DA), consistent with increased catecholamine biosynthesis during prolonged secretion. We found dilated mitochondrial cristae, endoplasmic reticulum and Golgi complex, as well as increased synaptic mitochondria, synaptic vesicles and glycogen granules in Chga-KO mice compared to WT mice, suggesting that decreased granulogenesis and catecholamine storage in CgA-deficient mouse adrenal medulla is compensated by increased VMAT-dependent catecholamine update into storage vesicles, at the expense of enhanced energy expenditure by the chromaffin cell. [ABSTRACT FROM AUTHOR]

Neuronal and neuroendocrine cells possess the capacity for Ca-regulated discharge of messenger molecules, which they release into synapses or the blood stream, respectively. The neural-crest-derived sympathoadrenal lineage gives rise to the sympathetic neurons of the autonomic nervous system and the neuroendocrine chromaffin cells of the adrenal medulla. These cells provide an excellent model system for studying common and distinct developmental mechanisms underlying the acquisition of neuroendocrine and neuronal properties. As catecholaminergic cells, they possess common markers related to noradrenaline synthesis, storage and release, but they also display diverging gene expression patterns and are morphologically and functionally different. The precise mechanisms that underlie the diversification of sympathoadrenal cells into neurons and neuroendocrine cells are not fully understood. However, in the past we could show that the establishment of a chromaffin phenotype does not depend on signals from the adrenal cortex and that chromaffin cells and sympathetic neurons apparently differ from the onset of their catecholaminergic differentiation. Nevertheless, the cues that specifically induce neuroendocrine features remain elusive. The early development of the progenitors of chromaffin cells and sympathetic neurons depends on a common set of transcription factors with overlapping but distinct influences on their development. In addition to the well-defined role of transcription factors as developmental regulators, our understanding of post-transcriptional gene regulation by microRNAs has substantially increased within the last few decades. This review highlights the major similarities and differences between chromaffin cells and sympathetic neurons, summarizes our current knowledge of the roles of selected transcription factors, microRNAs and environmental signals for the neuroendocrine differentiation of sympathoadrenal cells, and draws comparisons with the development of other endocrine and neuronal cells. [ABSTRACT FROM AUTHOR]

Deciphering the core machinery of the cell cycle and cell division has been primarily the focus of cell biologists, while developmental biologists have identified the signaling pathways and transcriptional programs controlling cell fate choices. As a result, until recently, the interplay between these two fundamental aspects of biology have remained largely unexplored. Increasing data show that the cell cycle and regulators of the core cell cycle machinery are important players in cell fate decisions during neurogenesis. Here, we summarize recent data describing how cell cycle dynamics affect the switch between proliferation and differentiation, with an emphasis on the roles played by the cell cycle regulators, the CDC25 phosphatases. [ABSTRACT FROM AUTHOR]

With the establishment of the 'neuron theory' at the turn of the twentieth century, this remarkably powerful term was introduced to name a breathtaking diversity of cells unified by a characteristic structural compartmentalization and unique information processing and propagating features. At the beginning of the twenty-first century, developmental, stem cell and reprogramming studies converged to suggest a common mechanism involved in the generation of possibly all vertebrate, and at least a significant number of invertebrate, neurons. Sox and, in particular, SoxB and SoxC proteins as well as basic helix-loop-helix proteins play major roles, even though their precise contributions to progenitor programming, proliferation and differentiation are not fully resolved. In addition to neuronal development, these transcription factors also regulate sensory receptor and endocrine cell development, thus specifying a range of cells with regulatory and communicative functions. To what extent microRNAs contribute to the diversification of these cell types is an upcoming question. Understanding the transcriptional and post-transcriptional regulation of genes coding for cell type-specific cytoskeletal and motor proteins as well as synaptic and ion channel proteins, which mark differences but also similarities between the three communicator cell types, will provide a key to the comprehension of their diversification and the signature of 'generic neuronal' differentiation. Apart from the general scientific significance of a putative universal core instruction for neuronal development, the impact of this line of research for cell replacement therapy and brain tumor treatment will be of considerable interest. [ABSTRACT FROM AUTHOR]

The cells that constitute the sympathetic nervous system originate from the neural crest. This review addresses the current understanding of sympathetic ganglion development viewed from molecular and morphological perspectives. Development of the sympathetic nervous system is categorized into three main steps, as follows: (1) differentiation and migration of cells in the neural crest lineage for formation of the primary sympathetic chain, (2) differentiation of sympathetic progenitors, and (3) growth and survival of sympathetic ganglia. The signaling molecules and transcription factors involved in each of these developmental stages are elaborated mostly on the basis of the results of targeted mutation of respective genes. Analyses in mutant mice revealed differences between the superior cervical ganglion (SCG) and the other posterior sympathetic ganglia. This review provides a summary of the similarities and differences in the development of the SCG and other posterior sympathetic ganglia. Relevant to the development of sympathetic ganglia is the demonstration that neuroendocrine cells, such as adrenal chromaffin cells and carotid body glomus cells, share a common origin with the sympathetic ganglia. Neural crest cells at the trunk level give rise to common sympathoadrenal progenitors of sympathetic neurons and chromaffin cells, while progenitors segregated from the SCG give rise to glomus cells. After separation from the sympathetic primordium, the progenitors of both chromaffin cells and glomus cells colonize the anlage of the adrenal gland and carotid body, respectively. This review highlights the biological properties of chromaffin cells and glomus cells, because, although both cell types are derivatives of sympathetic primordium, they are distinct in many respects. [ABSTRACT FROM AUTHOR]

Neurotrophic factors are operationally defined as molecules that promote the survival and differentiation of neurons. Chemically, they belong to divergent classes of molecules but most of the classic neurotrophic factors are proteins. Together with stem cells, viral vectors and genetically engineered cells, they constitute important tools in neuroprotective and regenerative neurobiology. Protein neurotrophic molecules signal through receptors located on the cell membrane. Their downstream signaling exploits pathways that are often common to chemically different factors and frequently target a relatively restricted set of transcription factors, RNA interference and diverse molecular machinery involved in the life vs. death decisions of neurons. Application of neurotrophic factors with the aim of curing or, at least, improving the outcome of neurodegenerative diseases requires (1) profound knowledge of the complex molecular pathology of the disease, (2) the development of animal models as closely as possible resembling the human disease, (3) the identification of target cells to be addressed, (4) intense efforts in chemical engineering to ensure the stability of molecules or to design carriers and small analogs with the ability to cross the blood-brain barrier and (5) scrutinity with regard to possible side effects. Last, but not least, engineering efforts to optimize administration, e.g., by designing the right canulae and infusion devices, are important for the successful translation of preclinical advances into clinical benefit. This article presents selected examples of neurotrophic factors that are currently being tested in animal models or developed for transfer to the clinic, with a major focus on factors with the potential of becoming applicable in various forms of retinal degeneration. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is an autoimmune disease that leads to oligodendrocyte loss and subsequent demyelination of the adult central nervous system (CNS). The pathology is characterized by transient phases of recovery during which remyelination can occur as a result of resident oligodendroglial precursor and stem/progenitor cell activation. However, myelin repair efficiency remains low urging the development of new therapeutical approaches that promote remyelination activities. Current MS treatments target primarily the immune system in order to reduce the relapse rate and the formation of inflammatory lesions, whereas no therapies exist in order to regenerate damaged myelin sheaths. During the last few years, several transplantation studies have been conducted with adult neural stem/progenitor cells and glial precursor cells to evaluate their potential to generate mature oligodendrocytes that can remyelinate axons. In parallel, modulation of the endogenous progenitor niche by neural and mesenchymal stem cell transplantation with the aim of promoting CNS progenitor differentiation and myelination has been studied. Here, we summarize these findings and discuss the properties and consequences of the various molecular and cell-mediated remyelination approaches. Moreover, we address age-associated intrinsic cellular changes that might influence the regenerative outcome. We also evaluate the extent to which these experimental treatments might increase the regeneration capacity of the demyelinated human CNS and hence be turned into future therapies. [ABSTRACT FROM AUTHOR]

Degeneration of the axon is an important step in the pathomechanism of traumatic, inflammatory and degenerative neurological diseases. Increasing evidence suggests that axonal degeneration occurs early in the course of these diseases and therefore represents a promising target for future therapeutic strategies. We review the evidence for axonal destruction from pathological findings and animal models with particular emphasis on neurodegenerative and neurotraumatic disorders. We discuss the basic morphological and temporal modalities of axonal degeneration (acute, chronic and focal axonal degeneration and Wallerian degeneration). Based on the mechanistic concepts, we then delineate in detail the major molecular mechanisms that underlie the degenerative cascade, such as calcium influx, axonal transport, protein aggregation and autophagy. We finally concentrate on putative therapeutic targets based on the mechanistic prerequisites. [ABSTRACT FROM AUTHOR]

Limited axonal plasticity within the central nervous system (CNS) is a major restriction for functional recovery after CNS injury. The small GTPase RhoA is a key molecule of the converging downstream cascade that leads to the inhibition of axonal re-growth. The Rho-pathway integrates growth inhibitory signals derived from extracellular cues, such as chondroitin sulfate proteoglycans, Nogo-A, myelin-associated glycoprotein, oligodendrocyte-myelin glycoprotein, Ephrins and repulsive guidance molecule-A, into the damaged axon. Consequently, the activation of RhoA results in growth cone collapse and finally outgrowth failure. In turn, the inhibition of RhoA-activation blinds the injured axon to its growth inhibitory environment resulting in enhanced axonal sprouting and plasticity. This has been demonstrated in various CNS-injury models for direct RhoA-inhibition and for downstream/upstream blockade of the RhoA-associated pathway. In addition, RhoA-inhibition reduces apoptotic cell death and secondary damage and improves locomotor recovery in clinically relevant models after experimental spinal cord injury (SCI). Unexpectedly, a subset of 'small molecules' from the group of non-steroid anti-inflammatory drugs, particularly the FDA-approved ibuprofen, has recently been identified as (1) inhibiting RhoA-activation, (2) enhancing axonal sprouting/regeneration, (3) protecting 'tissue at risk' (neuroprotection) and (4) improving motor recovery confined to realistic therapeutical time-frames in clinically relevant SCI models. Here, we survey the effect of small-molecule-induced RhoA-inhibition on axonal plasticity and neurofunctional outcome in CNS injury paradigms. Furthermore, we discuss the body of preclinical evidence for a possible clinical translation with a focus on ibuprofen and illustrate putative risks and benefits for the treatment of acute SCI. [ABSTRACT FROM AUTHOR]

Axonal regeneration is inhibited by a plethora of different mechanisms in the adult central nervous system (CNS). While neurotrophic factors have been shown to stimulate axonal growth in numerous animal models of nervous system injury, a lack of suitable growth substrates, an insufficient activation of neuron-intrinsic regenerative programs, and extracellular inhibitors of regeneration limit the efficacy of neurotrophic factor delivery for anatomical and functional recovery after spinal cord injury. Thus, growth-stimulating factors will likely have to be combined with other treatment approaches to tap into the full potential of growth factor therapy for axonal regeneration. In addition, the temporal and spatial distribution of growth factors have to be tightly controlled to achieve biologically active concentrations, to allow for the chemotropic guidance of axons, and to prevent adverse effects related to the widespread distribution of neurotrophic factors. Here, we will review the rationale for combinatorial treatments in axonal regeneration and summarize some recent progress in promoting axonal regeneration in the injured CNS using such approaches. [ABSTRACT FROM AUTHOR]

The ability of injured peripheral nerves to regenerate and reinnervate their original targets is a characteristic feature of the peripheral nervous system (PNS). On the other hand, neurons of the central nervous system (CNS), including retinal ganglion cell (RGC) axons, are incapable of spontaneous regeneration. In the adult PNS, axonal regeneration after injury depends on well-orchestrated cellular and molecular processes that comprise a highly reproducible series of degenerative reactions distal to the site of injury. During this fine-tuned process, named Wallerian degeneration, a remodeling of the distal nerve fragment prepares a permissive microenvironment that permits successful axonal regrowth originating from the proximal nerve fragment. Therefore, a multitude of adjusted intrinsic and extrinsic factors are important for surviving neurons, Schwann cells, macrophages and fibroblasts as well as endothelial cells in order to achieve successful regeneration. The aim of this review is to summarize relevant extrinsic cellular and molecular determinants of successful axonal regeneration in rodents that contribute to the regenerative microenvironment of the PNS. [ABSTRACT FROM AUTHOR]

The robust axon regeneration that occurs following peripheral nerve injury is driven by transcriptional activation of the regeneration program and by the expression of a wide range of downstream effector molecules from neuropeptides and neurotrophic factors to adhesion molecules and cytoskeletal adaptor proteins. These regeneration-associated effector molecules regulate the actin-tubulin machinery of growth-cones, integrate intracellular signalling and stimulatory and inhibitory signals from the local environment and translate them into axon elongation. In addition to the neuronally derived molecules, an important transcriptional component is found in locally activated Schwann cells and macrophages, which release a number of cytokines, growth factors and neurotrophins that support neuronal survival and axonal regeneration and that might provide directional guidance cues towards appropriate peripheral targets. This review aims to provide a comprehensive up-to-date account of the transcriptional regulation and functional role of these effector molecules and of the information that they can give us with regard to the organisation of the regeneration program. [ABSTRACT FROM AUTHOR]

The intercellular cell adhesion molecule-1 (ICAM-1) has been implicated in the recruitment of immune cells during inflammatory processes. Previous studies investigating its involvement in the process of Wallerian degeneration and focusing on its potential role in macrophage recruitement have come to controversial conclusions. To examine whether Wallerian degeneration is altered in the absence of ICAM-1, we have analyzed changes in the expression of axonal and Schwann cell markers following sciatic nerve crush in wildtype and ICAM-1-deficient mice. We report that the lack of ICAM-1 leads to impaired axonal degeneration and regeneration and to alterations in Schwann cell responses following sciatic nerve crush. Degradation of neurofilament protein, the collapse of axonal profiles, and the re-expression of neurofilament proteins are substantially delayed in the distal nerve segment of ICAM-1-/- mice. In contrast, the degradation of myelin, as determined by immunostaining for myelin protein zero, is unaltered in the mutants. Upregulation of GAP-43 and p75 neurotrophin receptor (p75NTR) expression, characteristic for Schwann cells dedifferentiating in response to nerve injury, is differentially altered in the mutant animals. These results indicate that ICAM-1 is essential for the normal progression of axonal degeneration and regeneration in distal segments of injured peripheral nerves. [ABSTRACT FROM AUTHOR]

Manipulation of neurotrophin (NT) signalling by administration or depletion of NTs, by transgenic overexpression or by deletion of genes coding for NTs and their receptors has demonstrated the importance of NT signalling for the survival and differentiation of neurons in sympathetic and dorsal root ganglia (DRG). Combination with mutation of the proapoptotic Bax gene allows the separation of survival and differentiation effects. These studies together with cell culture analysis suggest that NT signalling directly regulates the differentiation of neuron subpopulations and their integration into neural networks. The high-affinity NT receptors trkA, trkB and trkC are restricted to subpopulations of mature neurons, whereas their expression at early developmental stages largely overlaps. trkC is expressed throughout sympathetic ganglia and DRG early after ganglion formation but becomes restricted to small neuron subpopulations during embryogenesis when trkA is turned on. The temporal relationship between trkA and trkC expression is conserved between sympathetic ganglia and DRG. In DRG, NGF signalling is required not only for survival, but also for the differentiation of nociceptors. Expression of neuropeptides calcitonin gene-related peptide and substance P, which specify peptidergic nociceptors, depends on nerve growth factor (NGF) signalling. ret expression indicative of non-peptidergic nociceptors is also promoted by the NGF-signalling pathway. Regulation of TRP channels by NGF signalling might specify the temperature sensitivity of afferent neurons embryonically. The manipulation of NGF levels “tunes” heat sensitivity in nociceptors at postnatal and adult stages. Brain-derived neurotrophic factor signalling is required for subpopulations of DRG neurons that are not fully characterized; it affects mechanical sensitivity in slowly adapting, low-threshold mechanoreceptors and might involve the regulation of DEG/ENaC ion channels. NT3 signalling is required for the generation and survival of various DRG neuron classes, in particular proprioceptors. Its importance for peripheral projections and central connectivity of proprioceptors demonstrates the significance of NT signalling for integrating responsive neurons in neural networks. The molecular targets of NT3 signalling in proprioceptor differentiation remain to be characterized. In sympathetic ganglia, NGF signalling regulates dendritic development and axonal projections. Its role in the specification of other neuronal properties is less well analysed. In vitro analysis suggests the involvement of NT signalling in the choice between the noradrenergic and cholinergic transmitter phenotype, in the expression of various classes of ion channels and for target connectivity. In vivo analysis is required to show the degree to which NT signalling regulates these sympathetic neuron properties in developing embryos and postnatally. [ABSTRACT FROM AUTHOR]

Mechanisms that regulate neural stem cell activity in the adult brain are tightly coordinated. They provide new neurons and glia in regions associated with high cellular and functional plasticity, after injury, or during neurodegeneration. Because of the proliferative and plastic potential of neural stem cells, they are currently thought to escape their physiological control mechanisms and transform to cancer stem cells. Signals provided by proteins of the transforming growth factor (TGF)-beta family might represent a system by which neural stem cells are controlled under physiological conditions but released from this control after transformation to cancer stem cells. TGF-beta is a multifunctional cytokine involved in various physiological and patho-physiological processes of the brain. It is induced in the adult brain after injury or hypoxia and during neurodegeneration when it modulates and dampens inflammatory responses. After injury, although TGF-beta is neuroprotective, it may limit the self-repair of the brain by inhibiting neural stem cell proliferation. Similar to its effect on neural stem cells, TGF-beta reveals anti-proliferative control on most cell types; however, paradoxically, many brain tumors escape from TGF-beta control. Moreover, brain tumors develop mechanisms that change the anti-proliferative influence of TGF-beta into oncogenic cues, mainly by orchestrating a multitude of TGF-beta-mediated effects upon matrix, migration and invasion, angiogenesis, and, most importantly, immune escape mechanisms. Thus, TGF-beta is involved in tumor progression. This review focuses on TGF-beta and its role in the regulation and control of neural and of brain-cancer stem cells. [ABSTRACT FROM AUTHOR]

Neurturin (NRTN) is a neurotrophic factor required during development for normal cholinergic innervation of the heart, but whether NRTN continues to function in the adult heart is unknown. We have therefore evaluated NRTN expression in adult mouse heart and the association of NRTN receptors with intracardiac cholinergic neurons and nerve fibers. Mapping the regional distribution and density of cholinergic nerves in mouse heart was an integral part of this goal. Analysis of RNA from adult C57BL/6 mouse hearts demonstrated NRTN expression in atrial and ventricular tissue. Virtually all neurons in the cardiac parasympathetic ganglia exhibited the cholinergic phenotype, and over 90% of these cells contained both components of the NRTN receptor, Ret tyrosine kinase and GDNF family receptor α2 (GFRα2). Cholinergic nerve fibers, identified by labeling for the high affinity choline transporter, were abundant in the sinus and atrioventricular nodes, ventricular conducting system, interatrial septum, and much of the right atrium, but less abundant in the left atrium. The right ventricular myocardium contained a low density of cholinergic nerves, which were sparse in other regions of the working ventricular myocardium. Some cholinergic nerves were also associated with coronary vessels. GFRα2 was present in most cholinergic nerve fibers and in Schwann cells and their processes throughout the heart. Some cholinergic nerve fibers, such as those in the sinus node, also exhibited Ret immunoreactivity. These findings provide the first detailed mapping of cholinergic nerves in mouse heart and suggest that the neurotrophic influence of NRTN on cardiac cholinergic innervation continues in mature animals. [ABSTRACT FROM AUTHOR]

Brain-derived neurotrophic factor (BDNF) is a growth factor belonging to the family of neurotrophins. Although neurotrophins in the male genital organs have been well documented, their role in the biology of these organs is far from clear. In particular, little is known about the influence of sex hormones on neurotrophin expression. In the present study, using immunohistochemistry and enzyme-linked immunosorbent assay (ELISA), we investigated the distribution and tissue concentration of BDNF in the vas deferens and accessory male genital glands in normal and castrated rats. The expression of BDNF mRNA was also investigated. In normal rats, BDNF immunoreactivity was localized in the musculature of the vas deferens and vesicular gland and in the fibromuscular stromal cells of the prostate. In the ventral prostatic lobes, BDNF immunoreactivity was localized in basal, secretory and neuroendocrine epithelial cells. Innervating ganglia and nerves were immunoreactive in all the examined tracts. After castration, BDNF immunoreactivity increased in the musculature of the vesicular gland and in the fibromuscular stromal cells of both dorsal and ventral prostatic lobes. BDNF immunoreactivity also increased in the nerves. ELISA and reverse transcription/real-time polymerase chain reaction confirmed the findings of the immunohistochemical study. In the accessory glands, castration induced an increase of both BDNF tissue concentration and mRNA expression. These results suggest that BDNF is expressed in the internal male genital organs of the rat and that its expression is downregulated by androgen hormones. We hypothesize that the observed BDNF increases are related to the castration-induced regression of the sympathetic nerves. [ABSTRACT FROM AUTHOR]

Dopaminergic cells in the retina express the receptor for brain-derived neurotrophic factor (BDNF), which is the neurotrophic factor that influences the plasticity of synapses in the central nervous system. We sought to determine whether BDNF influences the network of dopaminergic amacrine cells in the axotomized rat retina, by immunocytochemistry with an anti-tyrosine hydroxylase (TH) antiserum. In the control retina, we found two types of TH-immunoreactive amacrine cells, type I and type II, in the inner nuclear layer adjacent to the inner plexiform layer (IPL). The type I amacrine cell varicosities formed ring-like structures in contact with AII amacrine cell somata in stratum 1 of the IPL. In the axotomized retinas, TH-labeled processes formed loose networks of fibers, unlike the dense networks in the control retina, and the ring-like structures were disrupted. In the axotomized retinas treated with BDNF, strong TH-immunoreactive varicosities were present in stratum 1 of the IPL and formed ring-like structures. Our data suggest that BDNF affects the expression of TH immunoreactivity in the axotomized rat retina and may therefore influence the retinal dopaminergic system. [ABSTRACT FROM AUTHOR]

We evaluated whether pericardial injections of the retrograde tracers cholera toxin subunit B (CTb) or Fast Blue (FB) reliably labelled cardiac vagal pre-ganglionic neurons. Injections of CTb into the pericardial space of the rat labelled neurons in both the external and compact formations of the nucleus ambiguus. Most labelled neurons were found in the compact formation of the nucleus ambiguus, and the majority of these, and only these, expressed immunoreactivity for calcitonin gene-related peptide. This distribution of labelled neurons and their immunohistochemical properties is characteristic of oesophageal motoneurons. Examination of the oesophagus following intra-pericardial CTb applications revealed strong labelling of motor end plates within the skeletal muscle of the thoracic but not the abdominal oesophagus. When a second retrograde tracer, FB, was injected into the abdominal oesophagus, labelled somata were found adjacent to CTb-labelled neurons in the compact formation of the nucleus ambiguus. No co-localisation of tracers was found, but identical proportions of calcitonin gene-related peptide (CGRP) immunoreactivity were observed in both groups of neurons. FB injected into the pericardial space labelled intra-cardiac neurons but not brainstem neurons. We conclude that intra-pericardial, and perhaps sub-epicardial, injections of some retrograde tracers are likely to label a subset of oesophageal, as well as cardiac, vagal motor neurons in the brainstem. [ABSTRACT FROM AUTHOR]

Neural crest cells that originate in the caudal hindbrain migrate into and along the developing gastrointestinal tract to form the enteric nervous system. While they are migrating, neural-crest-derived cells are also proliferating. Previous studies have shown that the expression of glial-derived neurotrophic factor (GDNF) and endothelin-3 is highest in the embryonic caecum, and that GDNF alone or in combination with endothelin-3 promotes the proliferation of enteric neural-crest-derived cells in vitro. However, whether neural proliferative zones, like those in the central nervous system, are found along the developing gut is unknown. We used a fluorescent nucleic acid stain to identify dividing cells or BrdU labelling (2 h after administration of BrdU to the mother), combined with antibodies specific to neural crest cells to determine the percentage of proliferating crest-derived cells in various gut regions of embryonic day 11.5 (E11.5) and E12.5 mice. The rate of proliferation of crest-derived cells did not vary significantly in different regions of the gut (including the caecum) or at different distances from the migratory wavefront of vagal crest-derived cells. The phenotype of mitotic enteric crest-derived cells was also examined. Cells expressing the pan-neuronal markers, neurofilament-M and Hu, or the glial marker, S100b, were observed undergoing mitosis. However, no evidence was found for proliferation of cells expressing neuron-type-specific markers, such as nitric oxide synthase (at E12.5) or calcitonin gene-related peptide (at E18.5). Thus, for enteric neurons, exit from the cell cycle appears to occur after the expression of pan-neuronal proteins but prior to the expression of markers of terminally differentiated neurons. [ABSTRACT FROM AUTHOR]

We have studied the role of endogenous neurotrophins in the formation and maturation of intrinsic hippocampal connections in vivo and analyzed the dentate granule cell projections in bothtrkB(-/-) andtrkC(-/-) mice. Immunohistochemistry against calbindin did not show major alterations in the distribution of granule cell axons, which were located exclusively in the hilus and the stratum lucidum. However, the thickness of the stratum lucidum (mossy fiber termination zone) and the density of mossy fiber terminals were reduced in the absence of TrkB signaling. Electron-microscopic analyses showed that the fine structure of mossy terminals was altered in bothtrkB(-/-) andtrkC(-/-) mice. Mutant granule cell terminals were smaller than those in wild-type animals and showed a reduction in both the number of synaptic contacts and synaptic vesicles. Immunofluorescence assays demonstrated that the expression levels of most synaptic-associated proteins (v-SNAREs and t-SNAREs) were altered in the mossy fibers oftrkB- andtrkC-deficient mice. Our results therefore reveal that TrkB and TrkC signaling is required for the maturation of granule cell axons. [ABSTRACT FROM AUTHOR]

Neurological disorders in humans can be modeled in animals using standardized procedures that recreate specific pathogenic events and their behavioral outcomes. The development of animal models of Parkinson’s disease (PD) is important to test new neuroprotective agents and strategies. Such animal models of PD have to mimic, at least partially, a Parkinson-like pathology and should reproduce specific features of the human disease. PD is characterized by massive degeneration of dopaminergic neurons in the substantia nigra, the loss of striatal dopaminergic fibers and a dramatic reduction of the striatal dopamine levels. The formation of cytoplasmic inclusion bodies (Lewy bodies) in surviving dopaminergic neurons represents the most important neuropathological feature of PD. Furthermore, the massive striatal dopamine deficiency causes easily detectable motor deficits in PD patients, including bradykinesia, rigidity, and resting tremor, which are the cardinal symptoms of PD. Over the years, a broad variety of experimental models of PD were developed and applied in diverse species. This review focuses on the two most common “classical” toxin-induced PD models, the 6-hydroxy-dopamine (6-OHDA model) and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model. Both neurotoxins selectively and rapidly destroy catecholaminergic neurons, whereas in humans the PD pathogenesis follows a progressive course over decades. This discrepancy reflects one important and principal point of weakness related to most animal models. This review discusses the most important properties of 6-OHDA and MPTP, their modes of administration, and critically examines advantages and limitations of selected animal models. The new genetic and environmental toxin models of PD (e.g. rotenone, paraquat, maneb) are discussed elsewhere in this “special issue.” [ABSTRACT FROM AUTHOR]

Growth factors promoting survival of mesencephalic dopaminergic neurons are discussed in the context of their requirement during development and adulthood. The expression of growth factors should be detectable in the nigrostriatal system during critical periods of development, i.e., during the period of ontogenetic cell death and synaptogenesis and during neurite extension and neurotransmitter synthesis. Growth factors discussed include members of the family of glial-cell-line-derived neurotrophic factors (GDNF), neurotrophins, transforming growth factors beta, and low molecular compounds mimicking growth factor activities. To date, the available data support the notion that GDNF is a highly promising candidate, although GDNF-null mice lack a dopaminergic phenotype. There remains a possibility that endogenous dopaminotrophic factors remain to be discovered. [ABSTRACT FROM AUTHOR]

Parkinson’s disease (PD) is a frequent neurological disorder of the basal ganglia, which is characterized by the progressive loss of dopaminergic neurons mainly in the substantia nigra pars compacta (SNpc). Inflammatory processes have been shown to be associated with the pathogenesis of PD. Activated microglia, as well as to a lesser extent reactive astrocytes, are found in the area associated with cell loss, possibly contributing to the inflammatory process by the release of pro-inflammatory prostaglandins or cytokines. Further deleterious factors released by activated microglia or astrocytes are reactive oxygen species. On the other hand, they may mediate neuroprotective properties by the release of trophic factors or the uptake of glutamate. In this review, we will discuss the different aspects of activated glial cells and potential mechanisms that mediate or protect against cell loss in PD. [ABSTRACT FROM AUTHOR]

Like most neural systems, dopamine neurons of the substantia nigra undergo apoptotic natural cell death during development. In rodents, this occurs largely postnatally and is biphasic with an initial major peak just after birth and a second minor peak on postnatal day 14. As envisioned by classic neurotrophic theory, this event is regulated by interactions with the target of these neurons, the striatum, because a developmental target lesion results in an augmented natural cell death event with fewer nigral dopamine neurons surviving into adulthood. Until recently, the striatal target-derived neurotrophic factors providing developmental support of dopamine neurons were unknown, but there is now growing evidence that glial-cell-line-derived neurotrophic factor (GDNF) serves as a physiologic limiting neurotrophic factor for these neurons during the first phase of natural cell death. During this phase, intrastriatal injection of GDNF diminishes the natural cell death event and neutralizing antibodies augment it. Sustained overexpression of GDNF in the striatum throughout development in a unique double transgenic mouse model results in an increased number of dopamine neurons surviving the first phase of natural cell death. However, this increase does not persist into adulthood. Therefore, other factors or mechanisms must play important roles in the determination of the mature number of nigral dopamine neurons. Further elucidation of these mechanisms will be important in the development of neuroprotective and cell replacement therapies for Parkinson’s disease. [ABSTRACT FROM AUTHOR]

We investigated parvalbumin immunoreactivity (PA-IR) in the retinas of rats maintained on a 12:12 h light:dark cycle, or after being placed in constant darkness for 24–72 h. Retinas were harvested at zeitgeber and circadian times 02:00, 06:00, 10:00, 14:00, 18:00 and 22:00 h. PA-IR was found primarily in retinal amacrine cells of the AII subtype. In a light/dark cycle, PA-IR showed a clear rhythm, with a low near zeitgeber time (ZT) 10:00 h and a peak near ZT 18:00 h. The ratio of immunofluorescence intensities at these timepoints was >15-fold. When animals were kept in complete darkness for 1–3 days, the rhythm of PA-IR was still preserved, but was progressively reduced in amplitude. The rhythm of PA-IR inferred from immunohistochemical data was confirmed by Western blots. We conclude that PA-IR in the rat retina shows an underlying circadian rhythm that is enhanced by cyclic light. The regulation may involve translocation of the protein between cell compartments and/or new protein synthesis. [ABSTRACT FROM AUTHOR]

In the present study we investigated the effects of infantile/prepubertal chronic oestrogen treatment, chemical sympathectomy with guanethidine and combined sympathectomy and chronic oestrogen treatment on developing sensory nerves of the rat uterus. Changes in sensory innervation were assessed quantitatively on uterine cryostat tissue sections stained for calcitonin gene-related peptide (CGRP). Uterine levels of NGF protein, using immunohistochemistry and ELISA, and mRNA, using Northern blots and in situ hybridization, were also measured. Finally, levels of TrkA NGF receptor in sensory neurons of T13 and L1 dorsal root ganglia (DRG), which supply the uterus, were assessed using densitometric immunohistochemistry. These studies showed that: (1) chronic oestrogen treatment led to an 83% reduction in the intercept density of CGRP-immunoreactive nerves; (2) sympathectomy had no effect on the density of uterine sensory nerves or on the pattern of oestrogen-induced changes; (3) NGF mRNA and protein increased following sympathectomy or chronic oestrogen treatment; and (4) oestrogen produced increased intensity of labelling (28%) for TrkA receptors in small-diameter sensory neurons, but decreased labelling (13%) in medium-sized neurons, which represent the large majority of the DRG neurons supplying the upper part of the uterine horn. Contrary to expectations, increased levels of NGF after sympathectomy and oestrogen treatment did not lead to increased sensory innervation of the uterus. The possibility that alterations in neuronal levels of TrkA contribute to the lack of response of uterine sensory nerves to the oestrogen-induced increase in NGF levels is discussed. [ABSTRACT FROM AUTHOR]

We studied the distribution of Bis (Bcl-2 interacting death suppressor) protein in the adult rat brain and spinal cord using immunohistochemistry. Immunoreactivity was observed in specific neuronal populations in distinct nuclei. The most intensely labeled cells were associated with the motor system, including most cranial nerve motor nuclei, Purkinje cells of the cerebellum, the red nucleus, and the ventral motor neurons of the spinal cord. Bis protein was also expressed in several structures associated with the ventricular system, including the subventricular zone of the lateral ventricle and its rostral extension, in the subcommissural organ, and in tanycytes, radial glial cells in the hypothalamus. Using double-labeling techniques, Bis-immunoreactive cells in the rostral migratory stream, coexpressing Bcl-2, were confirmed as glial fibrillary acidic protein-positive astrocytes comprising the glial tubes. The widespread distribution of Bis suggests that this protein has broader functions in the adult rat central nervous system than previously thought, and that it could be associated with a particular role in the rostral migratory system. [ABSTRACT FROM AUTHOR]

Fibroblast growth factors (FGFs) and their receptors constitute an elaborate signaling system that participates in many developmental and repair processes of virtually all mammalian tissues. Among the 23 FGF members, ten have been identified in the brain. Four FGF receptors (FGFRs), receptor tyrosine kinases, are known so far. Ligand binding of these receptors greatly depends on the presence of heparan sulfate proteoglycans, which act as low affinity FGFRs. Ligand binding specificity of FGFRs depends on the third extracellular Ig-like domain, which is subject to alternative splicing. Activation of FGFRs triggers several intracellular signaling cascades. These include phosphorylation of src and PLCγ leading finally to activation of PKC, as well as activation of Crk and Shc. SNT/FRS2 serves as an alternative link of FGFRs to the activation of PKC and, in addition, activates the Ras signaling cascade. In the CNS, FGFs are widely expressed; FGF-2 is predominantly synthesized by astrocytes, whereas other FGF family members, e.g., FGF-5, FGF-8, and FGF-9, are primarily synthesized by neurons. During CNS development FGFs play important roles in neurogenesis, axon growth, and differentiation. In addition, FGFs are major determinants of neuronal survival both during development and during adulthood. Adult neurogenesis depends greatly on FGF-2. Finally, FGF-1 and FGF-2 seem to be involved in the regulation of synaptic plasticity and processes attributed to learning and memory. [ABSTRACT FROM AUTHOR]

Connective tissue growth factor (CTGF) is a potent fibroblast mitogen and angiogenic factor which plays an important role in wound healing, cancerogenesis and fibrotic and vascular disease. Here we explored the regulation and the cellular site of the mRNA synthesis for this growth factor in the developing mouse embryo by in situ hybridisation. Strong and persistent CTGF gene expression was limited to three types of tissue: the vascular endothelium, particularly the high-pressure part of the cardiovascular system, condensed connective tissue around bone and cartilage, and maturing layer VII neurons in the cerebral cortex. With few exceptions (late tooth bud, neuroepithelium) epithelial tissue was negative. Very transient but strong expression was observed early during formation of cartilage, in late stages during perichondral ossification, on cerebral neuroepithelium, and in several discrete stages of tooth formation, on mesenchymal precursors of odontoblasts condensing on inner dental epithelium, and later on apposing regions of ameloblast and odontoblast epithelium. Altogether, the current study suggests that CTGF performs a dual role: a continuous function in the cardiovascular system, bone and cartilage-associated mesenchyme and maturing layer VII neurons, but also a more transient function associated with the formation of cartilage, bone, tooth and cerebral nerve cells. [ABSTRACT FROM AUTHOR]

The three axon growth inhibitory proteins, myelin associated glycoprotein, oligodendrocyte-myelin glycoprotein and Nogo-A, can all bind to the Nogo-66 receptor (NgR). This receptor is expressed by neurons with high amounts in regions of high plasticity where Nogo expression is also high. We hypothesized that simultaneous presence of high levels of Nogo and its receptor in neurons confers a locked state to hippocampal and cortical microcircuitry and that one or both of these proteins must be effectively and temporarily downregulated to permit plastic structural changes underlying formation of long-term memory. Hence, we subjected rats to kainic acid treatment and exposed rats to running wheels and measured NgR mRNA levels by quantitative in situ hybridization at different time points. We also studied spinal cord injuries and quantified NgR mRNA levels in spinal cord and ganglia during a critical postnatal period using real-time PCR. Strikingly, kainic acid led to a strong transient downregulation of NgR mRNA levels in gyrus dentatus, hippocampus, and neocortex during a time when BDNF mRNA was upregulated instead. Animals exposed to running wheels for 3 and 7, but not 1 or 21, days showed a significant downregulation of NgR mRNA in cortex, hippocampus and the dentate gyrus. NgR mRNA levels decreased from high to low expression in spinal cord and ganglia during the first week of life. No robust regulation of NgR was observed in the spinal cord following spinal cord injury. Together, our data show that NgR levels in developing and adult neurons are regulated in vivo under different conditions. Strong, rapid and transient downregulation of NgR mRNA in response to kainic acid and after wheel running in cortex and hippocampus suggests a role for NgR and Nogo-A in plasticity, learning and memory. [ABSTRACT FROM AUTHOR]

Neurotrophic factors regulate survival, differentiation, growth and plasticity in the nervous system. In addition, based on their specific and shifting temporospatial expression patterns, neurotrophic factors have been implicated in morphogenetic events during tooth development in rodents. To determine whether these findings in rodents could be related to humans, we have now studied nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4 (NT-4), glial cell-line derived neurotrophic factor (GDNF), and neurturin (NTN) mRNA expression patterns in developing human teeth during gestational weeks 6.5–11. Using in situ hybridization histochemistry, we found distinct and specific patterns of neurotrophin and GDNF mRNA expression in the developing human teeth. NGF mRNA labeling was weak and confined predominantly to the dental papilla. BDNF mRNA labeling was stronger than NGF mRNA and was seen in the mesenchyme located lateral to the dental organ, as well as in epithelial structures (inner dental epithelium and enamel knot). NT-3 mRNA was observed in the dental papilla and in the area of the cervical loop. NT-4 mRNA was expressed in both oral and dental epithelia in all stages studied. GDNF mRNA was found in the dental follicle and at different sites in the inner dental epithelium. Weak NTN mRNA labeling was also found in the developing teeth. Based on these findings, we suggest that neurotrophins, GDNF and NTN might be involved in morphogenetic events during early stages of tooth development in humans. Protein gene product (PGP) 9.5-immunoreactive nerve fibers were observed in the dental follicle by 11 weeks coinciding with the labeling for neurotrophic factor mRNAs in this structure. This suggests that these neurotrophic factors might be involved in the innervation of dental structures. The rich expression of neurotrophic factors in developing dental tissues suggests that developing, or possibly adult, dental tissue might be used as an allograft source of trophic support for diseases of the nervous system. [ABSTRACT FROM AUTHOR]

Brain injuries trigger physiological reactions which are mediated by a number of cytokines including interleukin-6 (IL-6), ciliary neurotrophic factor (CNTF), and leukemia inhibitory factor (LIF). Astrocytes and microglia, the protagonists in these traumatic responses, are known to secrete a variety of paracrine signals. Oligodendrocytes are involved as well and constitute another possible source of cytokines. Here we show the expression of IL-6, CNTF, and LIF in OLN-93 cells, derived from rat oligodendrocyte primary cultures. While differential gene transcription after injury has been described for many cytokines, the regulation of these physiological responses is unknown in many instances. Recent experiments indicate that the transcriptional activator retinoic acid (RA) plays a role in peripheral nerve regeneration. Transcripts of the retinoic acid receptors and the retinoid X receptors were also detected in OLN-93 oligodendrocytes. Using quantitative RT-PCR, we have therefore investigated the effect of RA on the expression of neuropoietic cytokines in these cells. Treatment with 1 µM all-trans RA for 24 h increased the mRNA concentration of LIF by a factor of 3.1 (P<0.01). In contrast, RA had no significant effect on the expression of CNTF. The results suggest RA as a possible regulator of cytokine signaling in the CNS. [ABSTRACT FROM AUTHOR]

Both olfactory ensheathing cells (OECs) and Schwann cells have been shown to promote axonal regrowth and remyelination in the central (CNS) and peripheral nervous systems under experimental conditions. During development, OECs and Schwann cells emerge from the olfactory placode and the neural crest, respectively, thus sharing a common "peripheral" origin. Both cell types are known to express a number of different molecular markers in common, to display a similar morphological phenotype in culture and to respond to the same growth-promoting molecules. Contrary to Schwann cells, OECs are found in association with neuronal processes in the CNS constituting the olfactory nerve layer of the olfactory bulb. OECs maintain their growth-promoting capacity in the CNS during adult life supporting the lifelong axonal growth of olfactory receptor neurons. Thus, OECs are considered an intermediate cell type combining a "central" location with "peripheral" permissiveness. Recently, the regenerative potential of OECs has been demonstrated in a variety of studies. However, OECs are still less clearly defined than Schwann cells. On designing future therapeutical strategies for nerve injury and disease, the important question arises as to whether OECs and Schwann cells are comparable cell types or whether they, indeed, mediate specific effects, making either the one or the other suitable for special applications. The present review summarizes recent data on the in vitro and in vivo properties of OECs and critically compares the analogies and differences in the biology of both cell types relevant in the above-mentioned context. [ABSTRACT FROM AUTHOR]

Retinal explants of mouse embryos were cultured together with explants of different regions in the retinofugal pathway in order to investigate whether ventral temporal (VT) and dorsal nasal (DN) retinal neurites showed differential responses to regional-specific cues in the pathway. In the presence of the chiasm, biased outgrowth of retinal neurites was found in explants of both retinal regions, which was accompanied by a reduction in total neurite growth in the VT but not the DN retina. Such differential responses to the diffusible negative influence were also observed when explants of two retinal origins were cocultured with the ventral diencephalon, but were not found with the dorsal diencephalon that contains targets of the optic axons. Indeed, extensive neurite invasion was found in the dorsal diencephalic explants and this ingrowth was more prominent for VT than DN neurites, showing a difference in axons from a distinct position in the retina to contact-mediated stimulatory activity within the target nuclei. We conclude that neurites from different regions of the retina show differential responses to the regional-specific cues in the diencephalon. These cues exist in both diffusible and contact-mediated forms that may shape the characteristic course and organization of retinal axons in decision regions of the optic pathway and the visual targets. [ABSTRACT FROM AUTHOR]

Activation of sympathetic nerves increases circulating glucose and inhibits insulin release from the islet beta-cells, which might contribute to stress-related diabetes. Accordingly, we have shown previously that blockade of parasympathetic activity aggravates diabetes in alloxan-treated mice, suggesting that unopposed sympathetic activity impairs diabetes. In this study, we tested whether elimination of sympathetic nerve activity by chemical sympathectomy with 6-hydroxydopamine (6-OHDA; 60 mg/kg) ameliorates the diabetogenic effects of alloxan (50 mg/kg) in NMRI mice. Mice given alloxan alone developed manifest diabetes after 2 days, as indicated by hyperglycemia. The diabetes persisted throughout the 35-day study period. Pretreatment with 6-OHDA did not, however, affect the glucose levels or the low, 2-min in vivo insulin response to glucose (1 g/kg) after alloxan. In situ hybridization at day 35 revealed a significantly reduced grain area of insulin-mRNA in the alloxan-treated animals, which was not affected by 6-OHDA, and an altered islet architecture, with accumulation of glucagon cells in the central portion. Also 6-OHDA alone reduced the insulin mRNA area, but this was accompanied by an increase in the total islet area. We conclude that, in contrast to cholinergic inhibition, sympathectomy does not perturb the development of chemically induced diabetes in mice. Alone, however, sympathectomy reduces insulin gene expression and induces increased islet size, suggesting that sympathetic nerves are of importance for long-term islet function. [ABSTRACT FROM AUTHOR]

Mammalian ovarian function is regulated by both hormonal inputs and direct neural influences. Recent studies have shown that, in addition to the extrinsic innervation, the ovaries of nonhuman primates and a strain of rats contain a discrete population of intrinsic neurons. In the present study, we used histological and immunohistochemical approaches to identify the presence of neuronal cell bodies in the fetal and neonatal human ovary. Neurons containing neurofilament immunoreactivity were detected in the hilum and medulla of the ovary at all ages studied, ranging from 24 weeks of gestation to 10 months of postnatal age. Most of them coexpressed the low affinity neurotrophin receptor (p75NTR), and some were catecholaminergic, as determined by their content of immunoreactive tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis. The presence of intrinsic neurons in the human ovary, similar to those previously found in other species, indicates that they may be engaged in regulating common, phylogenetically conserved, ovarian functions. It also raises the possibility that their dysfunction may contribute to the manifestation of particular ovarian pathologies. [ABSTRACT FROM AUTHOR]