Developmental changes in concentrations and distributions of neurotrophins in the monkey cerebellar cortex

Neurotrophins are involved in the survival, differentiation, migration and neurite outgrowth of various neuronal populations. Neurotrophins and their receptors are widely expressed in the developing cerebellum of various experimental animals. To gain some insight into the possible roles played by these molecules in monkey cerebellum, we examined the protein levels of BDNF, NT-4/5 and NT-3 and distributions of those neurotrophins and TrkC, a high affinity receptor for NT-3, in the cerebellum of developing macaque monkeys using ELISAs and immunohistochemical methods. We found that the level of BDNF increased during development, while the level of NT-3 was higher during embryonic stages and decreased toward adulthood. The level of NT-4/5 increased from embryonic stages to infant stages and gradually declined with age. Among the three neurotrophins, BDNF immunoreactivity was found in all kinds of cerebellar neurons, including all inhibitory interneurons, throughout the postnatal periods examined, indicating that BDNF may be an essential factor for the maintenance of cerebellar neural functions. The Bergmann glial fibers and the internal part of the external granule cell layer were strongly NT-3 immunopositive at the early postnatal stages, and more weakly immunoreactive toward adulthood. In addition, we found that the premigratory precursors of the granule cells were TrkC immunopositive at early postnatal stages. These findings suggest that NT-3 in Bergmann glial fibers may be involved in the migration of the premigratory granule cells.     

Neurotrophins and their receptors in early development of the mammalian nervous system

Neurotrophins belonging to the class of growth factors and including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin-4/5 (NT-4/5) are widely recognized as essential factors in the developing central nervous system (CNS). Neurotrophins are synthesized as precursor forms (proneurotrophins). Mature forms of neurotrophins exert their effect by binding to specific tyrosine kinases receptors (TrkA, TrkB and TrkC) as well as via the p75 receptor, a member of the tumor necrosis factor receptor superfamily while proneurotrophins interact with the receptor p75 or co-receptor complex of p75 and sortilin, that is a Vps10p domain-containing transmembrane protein. Expression of neurotrophins corresponds with the onset of neurogenesis in developing mammalian species. BDNF is low in early embryonic stages of development, while NT-3 highly expresses in the developing CNS. Expression of neurotrophins receptors mainly overlaps at early development. Data concerning early distribution of neurotrophins and their receptors in the nervous system and results in mice with targeted disruptions of neurotrophin or receptor genes show that neurotrophins and their receptors play distinct roles in control and regulation of the most crucial developmental processes such as proliferation, migration, differentiation, survival, apoptosis and synaptic plasticity.     

Postnatal Development of the Central Nervous System: Anomalies in the Formation of Cerebellum Fissures

A natural defect in rat cerebellum postnatal development has been found in the fissura prima, consisting in various complex configurations of the cerebellar layers. We investigated the genesis of fissure malformations through immunoreactions for PCNA, GFAP, GABAA α6, and calbindin to label proliferating cells of the external granular layer (egl), radial glial fibers, mature granule cells, and Purkinje cells, respectively. Results on critical stages of rat postnatal development provided interesting evidences on how the malformation develops in fissures prima and secunda. Early (postnatal day 10) at the site of malformation, the Bergmann radial glia was often retracted and showed distortions and irregular running. The interruption of GFAP‐positive radial glial fibers could fit in with the presence of clusters of PCNA‐unlabeled cells in the sites of fusion of the egl; the clusters of cells are granule cells since their soma is labeled by GABAA α6. Moreover, an altered migration of granule cell precursors to the internal granular layer was evident which, in turn, affected Purkinje cell differentiation and the growth of their dendrites. In summary, the changed relationship among glial fiber morphology, granule cell migration, and Purkinje cell differentiation suggests how the Bergmann glial fibers have a basic role in the foliation process, being the driving physical force in directing migration of the granule cells at the base of fissure. Anat Rec, 2010. © 2010 Wiley‐Liss, Inc.     

Cytodifferentiation of bergmann glia and its relationship with purkinje cells

The Bergmann glia is composed of unipolar protoplasmic astrocytes in the cerebellar cortex. Bergmann glial cells locate their cell bodies around Purkinje cells, and extend radial or Bergmann fibers enwrapping synapses on Purkinje cell dendrites. During development, Bergmann fibers display a tight association with migrating granule cells, from which the concept of glia-guided neuronal migration has been proposed. Thus, it is widely known that the Bergmann glia is associated with granule cells in the developing cerebellum and with Purkinje cells in the adult cerebellum. As the information on how Bergmann glial cells are related structurally and functionally with differentiating Purkinje cells is quite fragmental, this issue has been investigated using cytochemical techniques for Bergmann glial cells. This review classifies the cytodiffer-entiation of Bergmann glial cells into four stages, that is, radial glia, migration, transformation and protoplasmic astrocytes, and then summarizes their structural relationship with Purkinje cells at each stage. The results conclude that the cytodifferentiation of Bergmann glial cells proceeds in correlation with the migration, dendritogenesis, synaptogenesis and maturation of Purkinje cells. Furthermore, morphological and molecular plasticity of this neuroglia appears to be regulated depending on the cytodifferentiation of nearby Purkinje cells. The functional relevance of this intimate neuron-glial relationship is also discussed with reference to recent studies in cell biology, cell ablation and gene knockout.     

小鼠放射状胶质细胞和小脑皮质的发育

目的探讨小鼠小脑皮质发育过程中放射状胶质细胞的分化。方法应用免疫荧光及5-溴脱氧尿嘧啶核苷(BrdU)检测技术,标记小鼠胚胎8d至生后180d小脑(57例,分为19组,每组3只)的神经干细胞、放射状胶质细胞、普肯耶细胞及颗粒细胞。结果放射状胶质细胞于胚胎13d的神经上皮出现,尔后该细胞分化为各种神经元和贝格曼胶质细胞,并在小脑皮质层状结构的形成中起着重要作用。结论放射状胶质细胞来源于神经上皮细胞,是神经细胞和神经胶质细胞的前体细胞。在小脑皮质的发育过程中,放射状胶质细胞能分化为普肯耶细胞和颗粒细胞,并为神经细胞的迁移提供路径和支架。     

Developmental analysis of GFAP immunoreactivity in the cerebellum of the meander tail mutant mouse

It is thought that Bergmann glial fibers assist in the inward migration of granule cells. Model systems in which there is a perturbation of either the migrating cells or the glial cell population have been useful in understanding the migratory process. In the meander tail mutant mouse, the anterior cerebellar region is agranular, whereas the posterior cerebellum is relatively unaffected by the mutation. This study presents a qualitative analysis of the development of cerebellar radial glia in mea/mea and +/mea mice aged from postnatal day 0 to adult, using an antibody against the glia specific antigen, glial fibrillary acidic protein. The results indicate a slight delay in the onset of immunoreactivity in the mea/mea cerebellum and abnormal glial formation in the anterior and posterior regions by postnatal day 5. At postnatal day 11, the full complement of labeled fibers appears to be present and although they appear abnormal in formation, they eventually reach the surface and terminate in oddly shaped and irregularly spaced endfeet. In adult mea/mea and +/mea mice, as compared to the early postnatal stages, there is a significant reduction in GFAP immunoreactive fibers. Cresyl violet stained adult mea/mea sections revealed the presence of ectopic granule cells in radial columns and small clumps at the surface of and within the molecular layer of the caudal cerebellum. Quantitative analyses revealed a 4- to 5-fold increase in the number of ectopic granule cells in lobule VIII of the mea/mea when compared with the +/mea cerebellum. These results suggest that the radial glia in the mea/mea cerebellum exhibit some uncharacteristic morphologies, but that these abnormalities are most likely the consequence of environmental alterations produced by the mutant gene.     

Developmental analysis of GFAP immunoreactivity in the cerebellum of the meander tail mutant mouse

It is thought that Bergmann glial fibers assist in the inward migration of granule cells. Model systems in which there is a perturbation of either the migrating cells or the glial cell population have been useful in understanding the migratory process. In the meander tail mutant mouse, the anterior cerebellar region is agranular, whereas the posterior cerebellum is relatively unaffected by the mutation. This study presents a qualitative analysis of the development of cerebellar radial glia in mea/mea and +/mea mice aged from postnatal day 0 to adult, using an antibody against the glia specific antigen, glial fibrillary acidic protein. The results indicate a slight delay in the onset of immunoreactivity in the mea/mea cerebellum and abnormal glial formation in the anterior and posterior regions by postnatal day 5. At postnatal day 11, the full complement of labeled fibers appears to be present and although they appear abnormal in formation, they eventually reach the surface and terminate in oddly shaped and irregularly spaced endfeet. In adult mea/mea and +/mea mice, as compared to the early postnatal stages, there is a significant reduction in GFAP immunoreactive fibers. Cresyl violet stained adult mea/mea sections revealed the presence of ectopic granule cells in radial columns and small clumps at the surface of and within the molecular layer of the caudal cerebellum. Quantitative analyses revealed a 4- to 5-fold increase in the number of ectopic granule cells in lobule VIII of the mea/mea when compared with the +/mea cerebellum. These results suggest that the radial glia in the mea/mea cerebellum exhibit some uncharacteristic morphologies, but that these abnormalities are most likely the consequence of environmental alterations produced by the mutant gene.     

Bergmann glial development in the mouse cerebellum as revealed by tenascin expression

Tenascin, an astroglia-derived extracellular matrix molecule, is also expressed by radial glia of the embryonic mouse cerebellum. Expression of tenascin can thus be applied as a marker of astroglial development from an early stage, especially prior to the expression of the glial fibrillary acidic protein (GFAP) that can be detected in the postnatal cerebellum. The development of Bergmann glia, specialized cerebello-cortical astroglia with radial processes, was examined by tenascin immunohistochemistry and non-radioactive in situ hybridization histochemistry for tenascin mRNA in the developing mouse cerebellum. Tenascin-immunopositive radial glial processes extending from the ventricular zone to the pia mater retracted toward the cortex in the embryonic cerebellum and occupied a position corresponding to the Bergmann glial processes at the perinatal stage. Tenascin gene-expressing cells were generated in the ventricular zone of the cerbellar primordium and migrated radially toward the cortex. They were stratified in the layer of Bergmann glial somata at the early postnatal stage. They extended GFAP-immunopositive radial processes from the somata to the pia mater as revealed by double-labeling employing tenascin in situ hybridization histochemistry and GFAP-immunostaining. Bergmann glia are therefore considered to develop from cerebellar radial glia by migration of their somata and retraction of their processes. The tenascin gene-expressing cells displayed mitotic activity after alignment in the cortex as revealed by double-labeling by tenascin in situ hybridization histochemistry and immunohistochemical detection of the incorporated bromodeoxyuridine. The above findings suggest that the Bergmann glia in the cortex represent one of the origins of the astroglia in the developing cerebellum.     

Effects of neurotrophins on human bronchial smooth muscle cell migration and matrix metalloproteinase-9 secretion

The neurotrophins nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) have been found to be upregulated in inflammatory pulmonary diseases, including asthma. The functional role for the neurotrophins in the airways is still not known, but it has been proposed that neurotrophins induce airway hyperreactivity and tissue remodeling. Bronchial smooth muscle cells have been suggested to be involved in the remodeling process through their capacity to proliferate, migrate, and secrete inflammatory mediators and matrix metalloproteinases (MMPs). Therefore, we studied the effect of NGF, BDNF, and NT-3 on human bronchial smooth muscle cell (HBSMC) migration and MMP-2 and MMP-9 secretion. Immunocytochemistry studies showed that HBSMCs expressed the neurotrophin receptors TrkA, TrkB, and TrkC. BDNF, NT-3, and NGF increased MMP-9, but not MMP-2, secretion as shown by zymography. BDNF and NT-3, but not NGF, stimulated HBSMC migration as evaluated by Boyden chamber. Taken together, our data indicate that the neurotrophins may stimulate events important for airway remodeling.     

Calcitonin gene-related peptide receptor expression in the neurons and glia of developing rat cerebellum: an autoradiographic and immunohistochemical analysis

Quantitative autoradiography (using [125I]human alpha-calcitonin gene-related peptide as a ligand) and immunofluorescence (using monoclonal antibodies directed against a purified receptor) followed by confocal analysis were applied to analyse the distribution and cellular localization of the calcitonin gene-related peptide receptor in the rat cerebellum during development. From late embryonic days to the end of the second postnatal week, during the time window of calcitonin gene-related peptide expression in climbing fibers, high levels of calcitonin gene-related peptide binding sites were found in the white matter, where immunolabeling was present in oligodendrocytes. Lower levels were found in the cerebellar cortex, where receptor immunolabeling was found in Bergmann glia in a presumptive cell surface location and, during the second postnatal week, also in the cytoplasm of Purkinje cells. From the end of the second postnatal week to adulthood, when calcitonin gene-related peptide is no longer present in climbing fibers, the number of calcitonin gene-related peptide binding sites increased in the molecular layer, where not only Bergmann glia but also Purkinje cell distal dendritic branchlets were immunolabeled in a presumptive cell surface location. Concomitantly, the number of calcitonin gene-related peptide binding sites sharply decreased in the white matter.The developmental expression of the calcitonin gene-related peptide receptor and the previously described proliferating/differentiating effects of the peptide on glial cells suggest that calcitonin gene-related peptide and its receptor may promote a coordinated development of cerebellar glial cells, an effect driven mainly by the calcitonin gene-related peptide released by climbing fibers. As a result of glia-neuron interactions, an indirect effect on the differentiation of the cerebellar neuronal circuitry is also likely to occur.     

Neurotrophins modulate monocyte chemotaxis without affecting macrophage function

Neurotrophins nerve growth factor (NGF), brain-derived growth factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin-4 (NT-4) and their high-affinity tyrosine protein kinase receptor (Trk) family, TrkA, TrkB, TrkC, and low-affinity p75(NTR) receptor, are key molecules implicated in the development of the central nervous system. Increasing evidence suggests that they also have physiological and pathological roles outside the nervous system. In this study we examined the expression of neurotrophins and their receptors in human activated macrophages and to what extent neurotrophins themselves modulate macrophage activation, in a model of primary adult monocyte-derived macrophage. Our data indicate that macrophages express neurotrophin and neurotrophin receptor genes differentially, and respond to cell stimulation by specific inductions. Neurotrophins did not modify the antigen-presenting capacities of macrophages or their production of proinflammatory cytokines, but somehow skewed their activation phenotype. In contrast, NGF clearly increased CXCR-4 expression in macrophage and their chemotactic response to low CXCL-12 concentration. The differential effect of specific macrophage stimuli on neurotrophin expression, in particular NGF and NT-3, and the specific enhancement of CXCR-4 expression suggest that neurotrophins might participate in tissue-healing mechanisms that should be investigated further in vivo.     

Cerebellar malformation obtained in rats by early postnatal treatment with 6-aminonicotinamide. Role of neuron-glia interactions in cerebellar development

To analyze the role of neuron-glia interactions during the organogenesis of the rat cerebellar cortex, the glial cells were damaged by the gliotoxic agent 6-aminonicotinamide. A single intraperitoneal injection in newborn rats produced a specific necrobiotic lesion of astrocytes and oligodendrocytes, but spared glial precursors. To allow the development of the cerebellar cortex in a situation in which most of the glial cells were damaged, 6-aminonicotinamide was injected several times during the first two postnatal weeks. Rats were killed at ages ranging between 6 and 26 days. In the youngest animals the lesion was very selective: Bergmann fibers, astrocytes and oligodendrocytes were necrotic or in an advanced stage of hydropic degeneration. Under these circumstances, granule cells were able to migrate. This migration occurred along the surface of severely altered Bergmann fibers. In rats aged 12–14 days the lesion was less selective; in addition to the glial damage, numerous pyknotic cells were observed among immature neurons of the external granular layer. Spared granule cells were still able to migrate, moving along necrotic Bergmann fibers. However, the migration was uneven; in a few folia, independent of the severity of the glial lesion, granule cells were stopped in their migration at the level of the Purkinje cell layer. This incomplete migration resulted in an inversion of the layering, Purkinje cells being adjacent to the white matter. In the oldest rats studied, a remnant of the external germinal layer was still present and the white matter was almost completely devoid of myelinated fibers. In most of the folia the layering was normal, although numerous ectopic granule cells were dispersed throughout the molecular layer. In a few folia, the inversion of the layering remained. At their level Purkinje cells have grown in an abnormal cellular environment. These cells exhibited altered patterns of dendritic arrangements, as well as disturbances in their synaptic investment (mossy fibers directly synapsed on Purkinje spines).These results demonstrate that, in spite of severe Bergmann fiber degeneration, granule cells are able to migrate. In addition, the analysis of Purkinje cells which have grown in an abnormal cellular milieu supports the view that local interactions are necessary to achieve the normal branching of their dendritic tree, and their synaptic investment.     

BDNF and NT-3 regulation of trkB and trkC mRNA levels in the developing chick spinal cord

In this study we investigated the effects of brain-derived neurotrophic factor (BDNF) and neurotrophin-3 on mRNA levels of TrkB and TrkC receptors. We used an expression system to supply developing chicks with the neurotrophic factor and then analysed the receptor mRNA levels at embryonic day 8 (E8), E10 and E15 using semi-quantitative RT-PCR. In control chicks, maximal expression levels of both receptors were observed at E10. Treatment with BDNF resulted in significant down-regulation of TrkB mRNA levels (P<0.05) at E10 but not E8 or E15. Treatment with NT-3 showed down-regulation of trkB levels at all developmental stages. TrkC mRNA levels were down-regulated at all developmental stages with NT-3 treatment and at E10 and E15 with BDNF treatment. For both receptors the down-regulation was greater in NT-3-treated chicks than those treated with BDNF. Thus, our data indicate that neurotrophin receptor mRNA levels in the spinal cord are regulated by neurotrophic factors during embryonic development.     

小鼠小脑皮质发育过程中细胞迁移及血管之间的相互作用

目的 探讨小鼠小脑片层化过程中血管发生与细胞迁移之间的关系。方法 不同年龄小鼠共计146只,应用免疫荧光法和5′-溴脱氧尿嘧啶核苷（BrdU）法及墨汁血管灌注技术,标记小鼠胚胎期10日（E10）至出生90日（P90）小脑的放射状胶质细胞,普肯耶细胞,颗粒细胞以及小脑内血管发生。结果 在E15左右,小脑皮质内开始出现血管网;尔后随着年龄的增长,放射状胶质细胞和血管之间相互诱导, 血管开始变得密集,我们可以观察到,外颗粒层的血管沿着放射状胶质细胞分布,但是在内颗粒层和白质,血管的走行比较紊乱,和放射状胶质细胞走行保持高度一致。结果还发现很多BrdU阳性细胞紧贴着血管迁移。结论 在小脑片层化形成的过程中,细胞迁移起着非常关键的作用,血管在小脑皮质内不仅和放射状胶质细胞相互作用,引导神经细胞的迁移,并且为神经细胞的迁移提供路径和支架。     

Reelin与小脑发育——Notch1信号通路的调节作用

目的 探讨Reelin在小脑放射状胶质细胞、神经干细胞和普肯耶细胞迁移和分布中的作用,并探讨Notch信号通路在其中的作用。 方法 取WT小鼠和reeler小鼠胚胎9d至生后60d的脑部共148例,运用免疫荧光技术检测两组小鼠小脑发育中放射状胶质细胞、神经干细胞、普肯耶细胞及激活型Notch1受体的表达。 结果 Reeler小鼠小脑发育中放射状胶质细胞极性紊乱导致迁移阻滞于内颗粒层,过早分化,分子层中数量减少(P<0.01);Sox2阳性的干细胞启动迁移较慢,随后未得到适当的终止信号越过普肯耶细胞层进入外颗粒层,野生型小鼠该细胞并不迁移进入外颗粒层;普肯耶细胞多数不能迁移至分子层大量阻滞于内颗粒层中形成细胞团;激活型的Notch1受体在reeler小鼠小脑中表达减少。 结论 Reelin在小脑神经干细胞、胶质细胞、普肯耶细胞发育和片层化分布中有重要作用,并且Notch1信号通路参与Reelin介导的小脑发育。     

Neurotrophin and Trk neurotrophin receptors in the inner ear of Salmo salar and Salmo trutta

Neurotrophins (NTs) and their signal transducing Trk receptors play a critical role in the development and maintenance of specific neuronal populations in the nervous system of higher vertebrates. They are responsible for the innervation of the inner ear cochlear and vestibular sensory epithelia. Neurotrophins and Trks are also present in teleosts but their distribution in the inner ear is unknown. Thus, in the present study, we used Western-blot analysis and immunohistochemistry to investigate the expression and cell localization of both NTs and Trk receptors in the inner ear of alevins of Salmo salar and Salmo trutta. Western-blot analysis revealed the occurrence of brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), but not nerve growth factor (NGF), as well as all three Trk receptors, i.e. TrkA, TrkB and TrkC, the estimated molecular weights of which were similar to those expected for mammals. Specific immunoreactivity for neurotrophins was detected mainly in the sensory epithelia. In particular, BDNF immunoreactivity was found in the maculae of the utricle and saccule, whereas NT-3 immunoreactivity was present in the sensory epithelium of the cristae ampullaris. As a rule the sensory epithelia of the inner ear lacked immunoreactivity for Trks, thus excluding possible mechanisms of autocrinia and/or paracrinia. By contrast, overlapping subpopulations of neurons in the statoacoustic ganglion expressed TrkA (about 15%), TrkB (about 65%) and TrkC (about 45%). The present results demonstrate that, as in mammals and birds, the inner ear of teleosts expresses the components of the neurotrophin-Trk system, but their roles remain to be elucidated.     

Neurotrophin and Neurotrophin Receptors in Vascular Smooth Muscle Cells: Regulation of Expression in Response to Injury

The neurotrophins, a family of related polypeptide growth factors including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin (NT)-3 and NT-4/5 promote the survival and differentiation of distinctive sets of embryonic neurons. Here we define a new functional role for neurotrophins, as autocrine or local paracrine mediators of vascular smooth muscle cell migration. We have identified neurotrophins, and their cognate receptors, the trk tyrosine kinases, in human and rat vascular smooth muscle cells in vivo. In vitro, cultured human smooth muscle cells express BDNF; NT-3; and trk A, B, and C Similarly, rat smooth muscle cells expressed all three trk receptors as well as all four neurotrophins. Moreover, NGF induces cultured human smooth muscle cell migration at subnanomolar concentrations. In the rat aortic balloon deendothelialization model of vascular injury, the expression of NGF, BDNF, and their receptors trk A and trk B increased dramatically in the area of injury within 3 days and persisted during the formation of the neointima. In human coronary atherosclerotic lesions, BDNF, NT-3, and NT-4/5, and the trk B and trk C receptors could be demonstrated in smooth muscle cells. These findings suggest that neurotrophins play an important role in regulating the response of vascular smooth muscle cells to injury.     

Stimulation of the inferior olivary complex alters the distribution of the type 1 corticotropin releasing factor receptor in the adult rat cerebellar cortex

In a previous study, it was shown that populations of climbing fibers, derived from the inferior olivary complex (IOC) contain the peptide corticotropin releasing factor (CRF) and that the expression of this peptide in climbing fibers could be modulated by the level of activity in olivary afferents. The intent of this study was to determine if there was comparable plasticity in the distribution of the type 1 CRF receptor (CRF-R1) in the cerebellum of the rat. Our results indicate that CRF-R1 was localized primarily to Purkinje cell somata and their primary dendrites and granule cells. In addition, scattered immunolabeling was present over the somata of Golgi cells, basket cells and stellate cells, as well as Bergmann glial cells and their processes. IOC stimulation for 30 min at 1 Hz increased CRF-R1 expression in molecular layer interneurons and processes of Bergmann glial cells. Little to no effect on CRF receptor distribution was observed in Purkinje cells, granule cells, or Golgi cells. IOC stimulation at 5 Hz however, increased CRF-R1 expression in the processes of Bergmann glial cells while decreasing its expression in basket, stellate and, to some extent, in Purkinje cells. The present results suggest that there is activity-dependent plasticity in CRF-R1 expression that must be considered in defining the mechanism by which the CRF family of peptides modulates activity in cerebellar circuits. The present results also suggest that the primary targets of CRF released from climbing fibers are Bergmann glial cells and interneurons in the molecular layer. Further, interneurons responded with a decrease in receptor expression following more intense levels of stimulation suggesting the possibility of internalization of the receptor. In contrast, Bergmann glial cells showed an increased expression in receptor expression. These data suggest that CRF released from climbing fibers may modulate the physiological properties of basket and stellate cells as well as having a heretofore unidentified and potentially unique effect on Bergmann glia.     

Functional expression of the TrkC gene,encoding a high affinity receptor for NT-3, in antigen-specific T helper type 2 (Th2) cells

Neurotrophins, including nerve growth factor, brain-derived neurotrophic factor and neurotrophin-3 (NT-3) are essential factors for the development of the nervous system. In this report, we demonstrate gene expression of neurotrophins and their receptors in T helper 1 (Th1) and T helper 2 (Th2) cells induced from na?ve CD4+ CD45RB+ T cells of ovalbumin-specific DO11.10 T cell receptor transgenic mice. Interestingly, the TrkC gene, which encodes a high affinity receptor for NT-3, was expressed in Th2 cells, but not in Th1 and na?ve CD4+ T cells. Expression of the TrkC gene was markedly augmented by addition of anti-IFN-gamma monoclonal antibody (mAb) into the culture, whereas it was blocked by anti-IL-4 mAb. Moreover, NT-3 synergistically enhanced anti-CD3 mAb-induced IL-4 production by Th2 cells, but did not affect IFN-gamma production by Th1 cells. These data suggest that NT-3, through its receptor TrkC, plays a critical role in regulating the Th1/Th2 balance.