Non-neural Cells Research Articles

Molecular and cellular characterization of Neuregulin‐1 type IV isoforms

Numerous genetic studies associated the Neuregulin 1 (NRG1) Icelandic haplotype (HAP(ice)), and its single nucleotide polymorphism SNP8NRG243177 [T/T], with schizophrenia. Because SNP8NRG243177 [T/T] has characteristics of a functional polymorphism that maps close to NRG1 type IV coding sequences, our initial goal was to map precisely the human type IV transcription initiation site. We determined that the initiation site is 23 bp upstream of the previously reported type IV exon, and that no other transcripts map to the SNP8NRG243177 region. Because NRG1 type IV transcripts are specific to human, we isolated full-length NRG1 type IV cDNAs from human hippocampi and expressed them in non-neural cells and dissociated rat hippocampal neurons to study protein expression, processing and function. Using an antiserum we generated against the NRG1 type IV-specific N-terminus, we found that the protein is targeted to the cell surface where PKC activation promotes its cleavage and release of the extracellular domain. Conditioned medium derived from type IV expressing cells stimulates ErbB receptor phosphorylation, as well as downstream Akt and Erk signaling, demonstrating that NRG1 type IV possesses biological activity similar to other releasable NRG1 isoforms. To study the subcellular targeting of distinct isoforms, neurons were transfected with the Ig-domain-containing NRG1 types I and IV, or the cysteine-rich domain type III isoform. Three dimensional confocal images from transfected neurons indicate that, whereas all isoforms are expressed on somato-dendritic membranes, only the type III-cysteine-rich domain isoform is detectable in distal axons. These results suggest that NRG1 type IV expression levels associated with SNP8NRG243177 [T/T] can selectively modify signaling of NRG1 released from somato-dendritic compartments, in contrast to the type III NRG1 that is also associated with axons.

Selected SALM (Synaptic Adhesion-Like Molecule) Family Proteins Regulate Synapse Formation

Synaptic cell adhesion molecules regulate various steps of synapse formation. Despite the great diversity of neuronal synapses, relatively few adhesion molecules with synaptogenic activity have been identified. Synaptic adhesion-like molecules (SALMs) are members of a family of cell adhesion molecules known to regulate neurite outgrowth and synapse maturation; however, the role of SALMs in synapse formation remains unknown. We found that expression of the SALM family proteins SALM3 and SALM5 in nonneural and neural cells induces both excitatory and inhibitory presynaptic differentiation in contacting axons. SALM3 and SALM5 proteins are enriched in synaptic fractions, and form strong (SALM3) or weak (SALM5) complexes with postsynaptic density-95 (PSD-95), an abundant postsynaptic scaffolding protein at excitatory synapses. Aggregation of SALM3, but not SALM5, on dendritic surfaces induces clustering of PSD-95. Knockdown of SALM5 reduces the number and function of excitatory and inhibitory synapses. These results suggest that selected SALM family proteins regulate synapse formation, and that SALM3 and SALM5 may promote synapse formation through distinct mechanisms.

Salivary glands as the source of plasma brain-derived neurotrophic factor in stressed rats engaged in biting behavior

Brain-derived neurotrophic factor (BDNF) is crucial for the survival and differentiation of the central and peripheral nervous systems. Recently, BDNF has been reported to exert broader biological activity on non-neural cells. A previous study examined the effect of immobilization stress on BDNF and its receptor tyrosine receptor kinase B in male rat submandibular glands. In the present study, we found that the rat submandibular gland is the major source of plasma BDNF during acute immobilization stress. Biting modulates the mRNA and protein levels of BDNF in the rat hippocampus, so we also investigated whether the plasma BDNF concentration is influenced by biting. Two hours of acute immobilization stress significantly increased the amount of BDNF mRNA within the rat submandibular glands. Moreover, allowing biting behavior for the second half of the 2-h stress exposure significantly increased the amount of salivary gland BDNF mRNA relative to stress alone. Similar results were found with plasma BDNF concentrations under the same conditions. We confirmed that biting during stress attenuates the increases in plasma adrenocorticotropic hormone and corticosterone concentrations, but this was not dependent on the submandibular glands. Increased BDNF, mRNA and protein expressions were observed in salivary duct cells as a result of immobilization stress and biting behavior, as demonstrated by real-time polymerase chain reaction, immunohistochemistry, western blotting, and enzyme-linked immunosorbent assay. Taken together, the findings indicate that the submandibular glands evidently contribute to the increase in plasma BDNF upon biting.

Reduced sympathetic neurite outgrowth on uterine tissue sections from rats treated with estrogen

In order to evaluate the contribution of substrate-bound factors to the extent and patterning of the sympathetic innervation of rat uterus following estrogen treatment, superior cervical ganglion explants from neonatal and adult ovariectomized rats were cultured on tissue sections of fresh frozen uterus from adult ovariectomized rats treated with estrogen or a vehicle. The main findings were: (1) neurite growth was greatly influenced by histological features of the underlying section; (2) on myometrial sections, neurites followed the orientation of the main axis of the longitudinally sectioned muscle cells; (3) neurites showed limited growth on transversally sectioned smooth muscle; (4) neuritic patterning was unaffected by a reduction in migrating ganglionic non-neuronal cells; (5) neurite outgrowth, but not non-neural cell migration, was markedly reduced on myometrial sections from rats treated with estrogen. These results suggest that adult myometrium continues to provide signals allowing the organotypic patterning and growth of sympathetic axons, that estrogen treatment modifies myometrial substrate properties so that it is less supportive for sympathetic neurite growth, and that adult sympathetic neurons retain their ability to recognize substrate-bound cues present in the myometrium. On endometrial sections, neurites formed radially symmetric halos, which were reduced in size on estrogen-treated endometrial substrates. Thus, changes in the neuritogenic capacity of the uterus underlie plasticity in uterine sympathetic nerves, and alterations in substrate-bound factors contribute to the diminished receptivity of the estrogenized uterus to its sympathetic innervation.

Histone Deacetylase Inhibitor Valproic Acid Inhibits Cancer Cell Proliferation via Down-regulation of the Alzheimer Amyloid Precursor Protein

The beta-amyloid precursor protein (APP) represents a type I transmembrane glycoprotein that is ubiquitously expressed. In the brain, it is a key player in the molecular pathogenesis of Alzheimer disease. Its physiological function is however less well understood. Previous studies showed that APP is up-regulated in prostate, colon, pancreatic tumor, and oral squamous cell carcinoma. In this study, we show that APP has an essential role in growth control of pancreatic and colon cancer. Abundant APP staining was found in human pancreatic adenocarcinoma and colon cancer tissue. Interestingly, treating pancreatic and colon cancer cells with valproic acid (VPA, 2-propylpentanoic acid), a known histone deacetylase (HDAC) inhibitor, leads to up-regulation of GRP78, an endoplasmic reticulum chaperone immunoglobulin-binding protein. GRP78 is involved in APP maturation and inhibition of tumor cell growth by down-regulation of APP and secreted soluble APPalpha. Trichostatin A, a pan-HDAC inhibitor, also lowered APP and increased GRP78 levels. In contrast, treating cells with valpromide, a VPA derivative lacking HDAC inhibitory properties, had no effect on APP levels. VPA did not modify the level of epidermal growth factor receptor, another type I transmembrane protein, and APLP2, a member of the APP family, demonstrating the specificity of the VPA effect on APP. Small interfering RNA-mediated knockdown of APP also resulted in significantly decreased cell growth. Based on these observations, the data suggest that APP down-regulation via HDAC inhibition provides a novel mechanism for pancreatic and colon cancer therapy.

Acid-sensing ion channel 1a mediates acid-induced increases in intracellular calcium in rat articular chondrocytes

Acid-sensing ion channels (ASICs) are cationic channels that are activated by extracellular acidification and implicated in pain perception, ischemic stroke, mechanosensation, learning, and memory. It has been shown that ASIC1a is an extracellular pH sensor in the central and peripheral nervous systems, but its physiological and pathological roles in non-neural cells are poorly understood. We demonstrated a novel physiological function of ASIC1a in rat articular chondrocytes. The expression of ASIC1a mRNA and protein in rat articular chondrocytes was evaluated by reverse transcriptase polymerase chain reaction (RT-PCR) and Western blotting. The distribution of ASIC1a protein located in articular chondrocytes was determined by using immunofluorescence cell staining. The possible molecular mechanisms of articular chondrocytes pH sensing, as assessed by recording intracellular calcium ([Ca(2+)]i) in chondrocytes, were analyzed by using the laser scanning confocal microscopy technique. The cell injury following acid exposure was analyzed with lactate dehydrogenase release assay and electron microscopy. mRNA and protein expression showed that ASIC1a was expressed abundantly in these cells. In cultured chondrocytes, extracellular pH 6.0 increased intracellular calcium in the presence of extracellular Ca(2+). The ASIC1a-specific blocker PcTX venom significantly reduced this increase in [Ca(2+)]i, and inhibited acid-induced articular chondrocyte injury. However, the increase in [Ca(2+)]i and articular chondrocyte injury were not observed in the absence of extracellular Ca(2+). These findings show that increased [Ca(2+)]i, mediated via ASIC1a, might contribute to acidosis-induced articular chondrocyte injury.

Dysbindin Promotes the Post-Endocytic Sorting of G Protein-Coupled Receptors to Lysosomes

BackgroundDysbindin, a cytoplasmic protein long known to function in the biogenesis of specialized lysosome-related organelles (LROs), has been reported to reduce surface expression of D2 dopamine receptors in neurons. Dysbindin is broadly expressed, and dopamine receptors are members of the large family of G protein-coupled receptors (GPCRs) that function in diverse cell types. Thus we asked if dysbindin regulates receptor number in non-neural cells, and further investigated the cellular basis of this regulation.Methodology/Principal FindingsWe used RNA interference to deplete endogenous dysbindin in HEK293 and HeLa cells, then used immunochemical and biochemical methods to assess expression and endocytic trafficking of epitope-tagged GPCRs. Dysbindin knockdown up-regulated surface expression of D2 receptors compared to D1 receptors, as reported previously in neurons. This regulation was not mediated by a change in D2 receptor endocytosis. Instead, dysbindin knockdown specifically reduced the subsequent trafficking of internalized D2 receptors to lysosomes. This distinct post-endocytic sorting function explained the minimal effect of dysbindin depletion on D1 receptors, which recycle efficiently and traverse the lysosomal pathway to only a small degree. Moreover, dysbindin regulated the delta opioid receptor, a more distantly related GPCR that is also sorted to lysosomes after endocytosis. Dysbindin was not required for lysosomal trafficking of all signaling receptors, however, as its depletion did not detectably affect down-regulation of the EGF receptor tyrosine kinase. Dysbindin co-immunoprecipitated with GASP-1 (or GPRASP-1), a cytoplasmic protein shown previously to modulate lysosomal trafficking of D2 dopamine and delta opioid receptors by direct interaction, and with HRS that is a core component of the conserved ESCRT machinery mediating lysosome biogenesis and sorting.Conclusions/SignificanceThese results identify a distinct, and potentially widespread function of dysbindin in promoting the sorting of specific GPCRs to lysosomes after endocytosis.

Treatment of human astrocytoma U87 cells with silicon dioxide nanoparticles lowers their survival and alters their expression of mitochondrial and cell signaling proteins

Recent evidence suggests silicon dioxide micro- and nanoparticles induce cytotoxic effects on lung cells. Thus, there is an increasing concern regarding their potential health hazard. Nevertheless, the putative toxicity of nanoparticles in mammalian cells has not yet been systematically investigated. We previously noted that several metallic oxide nanoparticles exert differential cytotoxic effects on human neural and nonneural cells. Therefore, we hypothesized that silicon dioxide nanoparticles induce cytotoxicity in U87 cells by lowering their survival by decreasing cell survival signaling and disturbing mitochondrial function. To investigate this hypothesis, we determined the activities of the key mitochondrial enzymes, citrate synthase and malate dehydrogenase, in astrocytoma U87 cells treated with silicon dioxide nanoparticles. In addition, we studied the expression of the mitochondrial DNA-encoded proteins, cytochrome C oxidase II and nicotinamide adenine dinucleotide (NADPH) dehydrogenase subunit 6, and cell signaling pathway protein extracellular signal-regulated kinase (ERK) and phosphorylated ERK in treated U87 cells. The activated form of ERK controls cell growth, differentiation, and proliferation. In parallel, we determined survival of U87 cells after treating them with various concentrations of silicon dioxide nanoparticles. Our results indicated that treatment with silicon dioxide nanoparticles induced decreases in U87 cell survival in a dose-related manner. The activities of citrate synthase and malate dehydrogenase in treated U87 cells were increased, possibly due to an energetic compensation in surviving cells. However, the expression of mitochondrial DNA-encoded cytochrome C oxidase subunit II and NADH dehydrogenase subunit 6 and the cell signaling protein ERK and phosphorylated ERK were altered in the treated U87 cells, suggesting that silicon dioxide nanoparticles induced disruption of mitochondrial DNA-encoded protein expression, leading to decreased mitochondrial energy production and decreased cell survival/proliferation signaling. Thus, our results strongly suggest that the cytotoxicity of silicon dioxide nanoparticles in human neural cells implicates altered mitochondrial function and cell survival/proliferation signaling.

Erythropoietin Improves Histological and Functional Outcomes after Traumatic Brain Injury in Mice in the Absence of the Neural Erythropoietin Receptor

Erythropoietin (EPO), essential for erythropoiesis, provides neuroprotection. The EPO receptor (EPOR) is expressed in both neural and non-neural cells in the brain. This study was designed to test the hypothesis that EPO provides beneficial therapeutic effects, even in the absence of the neural EPOR. In this study, EPOR-null mice were rescued with selective EpoR expression driven by the endogenous EpoR promoter in hematopoietic tissue, but not in the neural cells. Anesthetized young adult female EPOR-null and wild-type mice were subjected to traumatic brain injury (TBI) induced by controlled cortical impact. EPO (5000 U/kg) or saline was intraperitoneally administered at 6 h and 3 and 7 days post-injury. Sensorimotor and spatial learning functions were assessed. Expression of EPOR and its downstream signal proteins were evaluated by Western blot analysis. Our data demonstrated that EPO treatment significantly reduced cortical tissue damage and hippocampal cell loss, and improved spatial learning following TBI in both the wild-type and EPOR-null mice. EPO treatment significantly improved sensorimotor functional recovery, with better outcomes in the wild-type mice. EPO treatment upregulated anti-apoptotic proteins (p-Akt and Bcl-XL) in the ipsilateral hippocampus and cortex of the injured wild-type and EPOR-null mice. These data demonstrate that EPO significantly provides neuroprotection following TBI, even in the absence of EPOR in the neural cells, suggesting that its therapeutic benefits may be mediated through vascular protection.

Defining a PARticular Pathway of Neural Tube Closure

Mammalian neurulation is completed when the dorsolateral neural folds bend inwards, their tips make adhesive contacts across the midline, and the epithelia remodel to create a closed neural tube. Two recent papers (one by Camerer et al. in this issue of Developmental Cell) demonstrate a vital role for protease-activated G protein-coupled receptor signaling in these late closure events, opening up new avenues for exploring the molecular basis of mammalian neural tube morphogenesis.

Neural crest-derived stem cells

The neural crest is a transient embryonic structure in vertebrates that gives rise to most of the peripheral nervous system (PNS) and to several non-neural cell types, including smooth muscle cells of the cardiovascular system, pigment cells in the skin, and craniofacial bones, cartilage, and connective tissue. Although neural crest cells undergo developmental restrictions with time, at least some neural crest cells have the capacity to self-renew and display a developmental potential almost only topped by embryonic stem (ES) cells. Intriguingly, such neural crest-derived stem cells (NCSCs) are not only present in the embryonic neural crest, but also in various neural crest-derived tissues in the fetal and even adult organism. These postmigratory NCSCs functionally resemble their embryonic counterparts in their ability to differentiate into a variety of cell types. Because of their broad potential, the possibility to isolate NCSCs from easily accessible tissue, and the recent accomplishment to generate NCSC-like cells from human ES and induced pluripotent stem (iPS) cells, NCSCs have become an ideal model system to study stem cell biology in development and disease. Despite exciting achievements in the field, several pressing issues remain to be addressed, however, such as the mechanisms regulating expansion and fate decisions in NCSCs from different sources and the still unknown physiological roles of NCSCs in the adult organism.

Brain-Specific Deletion of Extracellular Signal-Regulated Kinase 2 Mitogen-Activated Protein Kinase Leads to Aberrant Cortical Collagen Deposition

The mitogen-activated protein kinases extracellular signal-regulated kinase (ERK)1 and 2 are essential intracellular mediators of numerous transmembrane signals. To investigate neural-specific functions of ERK2 in the brain, we used a Cre/lox strategy using Nestin:Cre to drive recombination in neural precursor cells. Nestin:Cre;ERK2(fl/fl) conditional knockout (cKO) mice have architecturally normal brains and no gross behavioral deficits. However, all cKO mice developed early-onset (postnatal day 35 to 40) frontal cortical astrogliosis, without evidence of neuronal degeneration. Frontoparietal cortical gray matter, but not underlying white matter, was found to contain abundant pericapillary and parenchymal reticulin fibrils, which were shown by immunohistochemistry to contain fibrillar collagens, including type I collagen. ERK1 general KO mice showed neither fibrils nor astrogliosis, indicating a specific role for ERK2 in the regulation of brain collagen. Collagen fibrils were also observed to a lesser extent in GFAP:Cre;ERK2(fl/fl) mice but not in CamKII-Cre;ERK2(fl/fl) mice (pyramidal neuron specific), consistent with a possible astroglial origin. Primary astroglial cultures from cKO mice expressed elevated fibrillar collagen levels, providing further evidence that the phenotype may be cell autonomous for astroglia. Unlike most other tissues, brain and spinal cord parenchyma do not normally contain fibrillar collagens, except in disease states. Determining mechanisms of ERK2-mediated collagen regulation may enable targeted suppression of glial scar formation in diverse neurological disorders.

Upregulation of Transient Receptor Potential Vanilloid Type-1 Receptor Expression in Oral Lichen Planus

Objectives: Oral lichen planus (OLP) is a chronic inflammatory disease of the oral mucosa. Its etiology is still unclear. Neurogenic components might contribute to the inflammatory process. The oral mucosa is richly innervated by sensory fibers. Mediators secreted by inflammatory cells activate sensory nerves via transient receptor potential vanilloid receptor 1 (TRPV1) and lead to the release of neuropeptides. So far, TRPV1 receptor expression was detected on neurons. Only recently, TRPV1 receptors were identified in nonneuronal tissues. The aim of the present study was to detect the presence of TRPV1 receptors and peripheral expression of receptor mRNA in normal oral mucosa and mucous membranes from OLP patients. Methods: Presence of TRPV1 receptor proteins in the mucosal tissue was assessed by immunohistochemistry. Expression of TRPV1 receptor mRNA was determined by quantitative RT-PCR. Results: We provided qualitative and quantitative immunohistochemical evidence that TRPV1 receptors are present in normal human oral mucosa and that their expression is increased in OLP. The number of immunopositive cells was elevated in the epithelium, and vascular endothelial cells, lymphocytes and fibroblasts of the subepithelium were also labeled in samples obtained from OLP patients. The local expression of nonneuronal TRPV1 receptors was proven at mRNA level using quantitative real-time RT-PCR. Conclusions: Since the number of TRPV1 receptor-positive nonneural cells is increased in inflammatory conditions, we hypothesize that TRPV1-receptor-mediated processes might play role in the pathogenesis of OLP.

Dissecting the functional significance of endothelin A receptors in peripheral nociceptors in vivo via conditional gene deletion

The peptide endothelin-1 (ET1), which was originally identified as a vasoconstrictor, has emerged as a critical regulator of a number of painful conditions, including inflammatory pain and tumor-associated pain. There is considerable pharmacological evidence supporting a role for endothelin A receptors (ET A) in mediating ET1-induced pro-algesic functions. ET A receptors are expressed in small-diameter nociceptive neurons, but also found in a variety of other cell types in peripheral tissues, including immune cells, keratinocytes, endothelial cells, which have the potential to modulate nociception. To elucidate the functional contribution of ET A receptors expressed in sensory neurons towards the functions of the ET1 axis in pathological pain states, we undertook a conditional gene deletion approach to selectively deplete expression of ET A in sensory nerves, preserving expression in non-neural peripheral tissues; the expression of ET B remained unchanged. Behavioural and pharmacological experiments showed that only late nociceptive hypersensitivity caused by ET1 is abrogated upon a loss of ET A receptors on nociceptors and further suggest that ET1-induced early nociceptive hypersensitivity involves activation of ET A as well as ET B receptors in non-neural peripheral cells. Furthermore, in the context of alleviation of cancer pain and chronic inflammatory pain by ET A receptor antagonists, we observed in corresponding mouse models that the contribution of ET A receptors expressed in nociceptors is most significant. These results help understand the role of ET A receptors in complex biological processes and peripheral cell–cell interactions involved in inflammatory and tumor-associated pain.

Autism: The Ups and Downs of Neuroligin

Autism: The Ups and Downs of Neuroligin

Alzheimer’s disease and Notch signaling

Cleavage of the amyloid precursor protein (APP) by γ-secretase generates a neurotoxic amyloid β-peptide (Aβ) that is thought to be associated with the neurodegeneration observed in Alzheimer’s disease (AD) patients. Presenilin is the catalytic member of the γ-secretase proteolytic complex and mutations in presenilins are the major cause of early-onset familial Alzheimer’s disease. In addition to APP, γ-secretase substrates include Notch1 homologues, Notch ligands Delta and Jagged, and additional type I membrane proteins, raising concerns about mechanism-based toxicities that might arise as a consequence of inhibiting γ-secretase. Notch signaling is involved in tumorigenesis as well as in determining the fates of neural and nonneural cells during development and in adults. Alterations in proteolysis of the Notch by γ-secretase could be involved in the pathogenesis of AD. Inconsistently, several recent observations have indicated that enhanced Notch signaling and expression could be instrumental in neurodegeneration in AD. Therefore, detailed and precise study of Notch signaling in AD is important for elucidating diverse mechanisms of pathogenesis and potentially for treating and preventing Alzheimer’s disease.

Cross-Talk Between Stem Cells and the Dysfunctional Brain is Facilitated by Manipulating the Niche: Evidence from an Adhesion Molecule

In the injured brain, the behavior of neural stem/progenitor cells (NSCs) is regulated by multiple converging factors encountered in the niche, which is composed of several neural and non-neural cell types. Signals emanating from the host influence the migration, survival, distribution, and fate of transplanted NSCs, which in turn can create host microenvironments that favor a return to homeostasis. We tested the hypothesis that overexpression of key facilitatory molecules that define the injury niche might enhance this bidirectional stem cell-host interaction to therapeutic advantage. As proof of concept, we investigated whether conditioning the niche with the neural cell adhesion molecule L1 might enhance recovery in a prototypical neurodegenerative milieu-the MPTP-induced model of Parkinson's disease in aged mice-where cross-talk between NSCs and imperiled host dopaminergic neurons is known to be pivotal in rescuing the function and connectivity of the latter. In lesioned mice (and in unlesioned controls), we overexpressed L1 in the NSCs to be transplanted into the ventral mesencephalon. Several pairwise experimental combinations were tested based on variations of engrafting L1 overexpressing versus nonoverexpressing NSCs into wild-type (WT) versus L1-overexpressing transgenic mice (specifically L1 transcribed from the GFAP promoter and, hence, overexpressed in host astrocytes). Enrichment for L1-particularly when expressed simultaneously in both donor NSCs and host brain-led to rapid and extensive distribution of exogenous NSCs, which in turn rescued (with an efficacy greater than in nonengineered controls) dysfunctional host dopaminergic nigral neurons, even when grafting was delayed by a month. L1 overexpression by NSCs also enhanced their own differentiation into tyrosine hydroxylase-expressing neurons in both WT and transgenic hosts. Graft-host interactions were thus favored by progressively increasing levels of L1. More broadly, this study supports the view that manipulating components of the niche (such as an adhesion molecule) that facilitate cross-talk between stem cells and the dysfunctional brain may offer new strategies for more efficacious neurotransplantation, particularly when treatment is delayed as in chronic lesions or advanced stages of a neurodegenerative disease.

Transplanted myogenic progenitor cells express neuronal markers in the CNS and ameliorate disease in Experimental Autoimmune Encephalomyelitis

This study explores the potential of non-neural progenitor cells for CNS cell therapy. Muscle progenitor cells (MPCs), transplanted either intraventricularly or intraperitonealy, incorporated into the CNS of EAE-induced but not of naïve mice. Some of the migrating MPCs expressed the neuronal marker β-III-Tubulin and gained neuronal morphology. Co-treatment of transplanted mice with the immunomodulatory agent glatiramer acetate (GA, Copaxone) resulted in improved MPCs incorporation and differentiation towards the neuronal pathway. The therapeutic potential of myogenic progenitor cells was demonstrated by amelioration of clinical symptoms and reduced mortality in EAE mice, as well as by expression of IL-10, TGF-β, and the neurotrophin-BDNF.

An infiltrative variant of non‐neural granular cell tumor: a case report

Dermal non-neural granular cell tumors are rare tumors of indeterminate lineage that typically present as well-circumscribed tumors with nuclear pleomorphism and mitotic activity. We describe a dermal non-neural granular cell tumor with a distinctive growth pattern with granular cells interspersed between collagen bundles. This asymptomatic papule arose on the scapula of a 46-year-old woman and consisted of a mixture of epithelioid and spindled granular cells. The immunohistochemical characteristics were similar to those of previously reported dermal non-neural granular cell tumors. Despite mild nuclear pleomorphism and dispersion of lesional cells among collagen bundles, mitoses were not present and Ki-67 staining indicated a low proliferative rate. In addition to being S-100 protein negative and NKI/C3 positive, our case was positive for PGP9.5 and weakly positive for neuron-specific enolase, a staining pattern similar to what has been observed for cellular neurothekeomas. Our case could represent a dermal non-neural granular cell tumor with unique architecture, a granular cellular neurothekeoma or a granular cell dermatofibroma. As both dermal non-neural granular cell tumor and cellular neurothekeoma are of indeterminate lineage, our case with features characteristic of both entities may suggest a common precursor or lineage for dermal non-neural granular cell tumor and cellular neurothekeoma.

The Insulin-Like Growth Factor (IGF) Receptor Type 1 (IGF1R) as an Essential Component of the Signalling Network Regulating Neurogenesis

The insulin-like growth factor receptor type 1 (IGF1R) signalling pathway is activated in the mammalian nervous system from early developmental stages. Its major effect on developing neural cells is to promote their growth and survival. This pathway can integrate its action with signalling pathways of growth and morphogenetic factors that induce cell fate specification and selective expansion of specified neural cell subsets. This suggests that during developmental and adult neurogenesis cellular responses to many signalling factors, including ligands of Notch, sonic hedgehog, fibroblast growth factor family members, ligands of the epidermal growth factor receptor, bone morphogenetic proteins and Wingless and Int-1, may be modified by co-activation of the IGF1R. Modulation of cell migration is another possible role that IGF1R activation may play in neurogenesis. Here, I briefly overview neurogenesis and discuss a role for IGF1R-mediated signalling in the developing and mature nervous system with emphasis on crosstalk between the signalling pathways of the IGF1R and other factors regulating neural cell development and migration. Studies on neural as well as on non-neural cells are highlighted because it may be interesting to test in neurogenic paradigms some of the models based on the information obtained in studies on non-neural cell types.