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Neurotrophins


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  • Overexpression of neurotrophin-3 stimulates a second wave of dopaminergic amacrine cell genesis after birth in the mouse retina. 21880927

    Dopaminergic amacrine (DA) cells play multiple and important roles in retinal function. Neurotrophins are known to modulate the number and morphology of DA cells, but the underlying regulatory mechanisms are unclear. Here, we investigate how neurotrophin-3 (NT-3) regulates DA cell density in the mouse retina. We demonstrate that overexpression of NT-3 upregulates DA cell number and leads to a consequent increase in the density of DA cell dendrites. To examine the mechanisms of DA cell density increase, we further investigate the effect of NT-3 overexpression on retinal apoptosis and mitosis during development. We find that NT-3 does not affect the well known wave of retinal cell apoptosis that normally occurs during the first 2 weeks after birth. Instead, overexpression of NT-3 promotes additional mitosis of DA cells at postnatal day 4, but does not affect cell mitosis before birth, the peak period of amacrine cell genesis in wild-type retinas. We next show that retinal explants cultured from birth to day 7 without extra NT-3 produced by lens exhibit similar number of DA cells as in wild type, further supporting the notion that postnatal overexpression of lens-derived NT-3 affects DA cell number. Moreover, the additional mitosis after birth in NT-3-overexpressing mice does not occur in calretinin-positive amacrine cells or PKC-positive rod ON bipolar cells. Thus, the NT-3-triggered wave of cell mitosis after birth is specific for the retinal DA cells.
    Tipo de documento:
    Referencia
    Referencia del producto:
    Múltiplo
    Nombre del producto:
    Múltiplo

  • Regulation of endosome dynamics by Rab5 and Huntingtin-HAP40 effector complex in physiological versus pathological conditions. 18413253

    Vesicular transport of signaling molecules, specifically neurotrophins, in neurons is essential for their differentiation, survival, and plasticity. Neurotrophins such as neuron growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are internalized by receptor-mediated endocytosis at synaptic terminals and loaded into endosomes for microtubule-based transport along axons to the cell body where they exert their signaling function in the nucleus. The molecular mechanisms underlying this intracellular transport are not only relevant from a basic knowledge viewpoint, but have also important implications for neurodegenerative diseases. Defects in trafficking are increasingly implicated in the pathology of Huntington's disease (HD) and other neurodegenerative disorders. The small GTPases Rab5 and Rab7 play important roles in the endocytic trafficking of neurotrophins. We have recently identified Huntingtin (Htt) and Huntingtin associated protein of 40 kDa (HAP40) as a novel Rab5 effector complex that regulates endosome motility. In HD, we detected higher HAP40 protein levels compared with normal cells. Such increase causes an augmented recruitment of Htt onto Rab5-positive early endosomes that drastically reduces their motility by switching these organelles from microtubules to F-actin. These findings suggest a mechanism by which impaired Rab5-mediated trafficking of neurotrophic factors may be a key event of the pathogenetic process leading to neurodegeneration in HD. To dissect the mechanisms by which Htt, HAP40, and Rab5 function in early endosome interactions with the cytoskeleton, we developed assays to investigate endosome-cytoskeleton interactions that can be applied to normal and pathological conditions. We provide here detailed protocols for, first, an assay that measures binding of early endosomes to microtubules and F-actin. Second, we describe an improved protocol for a cell-free assay that recapitulates the motility of early endosomes along microtubules in vitro. These assays provide mechanistic insights into the dysfunction of endosome motility occurring in HD as well as other neurodegenerative disorders.
    Tipo de documento:
    Referencia
    Referencia del producto:
    AB5872

  • Anterograde axonal transport of BDNF and NT-3 by retinal ganglion cells: roles of neurotrophin receptors. 15866043

    Retinal ganglion cells (RGCs) transport exogenous neurotrophins anterogradely to the midbrain tectum/superior colliculus with significant downstream effects. We determined contributions of neurotrophin receptors for anterograde transport of intraocularly injected radiolabeled neurotrophins. In adult rodents, anterograde transport of brain-derived neurotrophic factor (BDNF) was receptor-mediated, and transport of exogenous BDNF and neurotrophin-3 (NT-3) was more efficient, per RGC, in rodents than chicks. RT-PCR and Western blot analysis of purified murine RGCs showed that adult RGCs express the p75 receptor. Anterograde transport of BDNF or NT-3 was not diminished in p75 knock-out mice (with unaltered final numbers of RGCs), but BDNF transport was substantially reduced by co-injected trkB antibodies. In chick embryos, however, p75 antisense or co-injected p75 antibodies significantly attenuated anterograde transport of NT-3 by RGCs. Thus, neither BDNF nor NT-3 utilizes p75 for anterograde transport in adult rodent RGCs, while anterograde NT-3 transport requires the p75 receptor in embryonic chicken RGCs.
    Tipo de documento:
    Referencia
    Referencia del producto:
    MAB377
    Nombre del producto:
    Anti-NeuN Antibody, clone A60

  • Kidins220/ARMS is an essential modulator of cardiovascular and nervous system development. 22048169

    The growth factor family of neurotrophins has major roles both inside and outside the nervous system. Here, we report a detailed histological analysis of key phenotypes generated by the ablation of the Kinase D interacting substrate of 220 kDa/Ankyrin repeat-rich membrane spanning (Kidins220/ARMS) protein, a membrane-anchored scaffold for the neurotrophin receptors Trk and p75(NTR). Kidins220 is important for heart development, as shown by the severe defects in the outflow tract and ventricle wall formation displayed by the Kidins220 mutant mice. Kidins220 is also important for peripheral nervous system development, as the loss of Kidins220 in vivo caused extensive apoptosis of DRGs and other sensory ganglia. Moreover, the neuronal-specific deletion of this protein leads to early postnatal death, showing that Kidins220 also has a critical function in the postnatal brain.
    Tipo de documento:
    Referencia
    Referencia del producto:
    AB1530
    Nombre del producto:
    Anti-Peripherin Antibody

  • P75 nerve growth factor receptor is important for retrograde transport of neurotrophins in adult cholinergic basal forebrain neurons. 10625055

    The role of the p75 nerve growth factor receptor in the retrograde transport of neurotrophins in the adult CNS was investigated by comparing the transport of 125I-labeled neurotrophins by normal and p75 nerve growth factor receptor-deficient cholinergic septohippocampal neurons. In control mice, nerve growth factor was selectively transported from the hippocampal formation to the cholinergic neurons in the septum. Nerve growth factor labeling was found in three to four times as many septal cholinergic neuronal cell bodies than labeling for neurotrophin-3 or neurotrophin-4/5, and transported brain-derived neurotrophic factor was barely detectable. Cells were considered as labeled when the number of grains per cell exceeded five times background. In p75 nerve growth factor receptor-deficient mice, the number of cholinergic neurons labeled with each of the neurotrophins was reduced by 85-95%. Retrograde labeling of septohippocampal neurons with Fluorogold was not obviously reduced in p75 nerve growth factor receptor-deficient mice, suggesting that general transport mechanisms were not impaired. Despite the reduced neurotrophin transport, cholinergic neurons of p75 nerve growth factor receptor-deficient mice were larger than controls and had an apparently normal density of immunostaining for choline acetyltransferase. Since nerve growth factor is reportedly involved in size regulation and choline acetyltransferase expression, this raises the possibility that the retrograde transport itself is not essential for these events. Thus, p75 nerve growth factor receptor plays an important, although not exclusive, role in the transport of neurotrophins by cholinergic basal forebrain neurons, and retrograde transport of nerve growth factor may not be needed for regulating certain cellular processes.
    Tipo de documento:
    Referencia
    Referencia del producto:
    AB143
    Nombre del producto:
    Anti-Choline Acetyltransferase (ChAT) Antibody

  • Trk receptors function as rapid retrograde signal carriers in the adult nervous system. 9278536

    During development target-derived neurotrophins promote the survival of neurons. However, mature neurons no longer depend on the target for survival. Do target-derived neurotrophins retain retrograde signaling functions in mature neurons, and, if so, how are they executed? We addressed this question by using a phosphotyrosine-directed antibody to locate activated Trk receptors in adult rat sciatic nerve. We show that catalytically active Trk receptors are located within the axon of adult rat sciatic nerve and that they are distributed throughout the length of the axons. These catalytically active receptors are phosphorylated on tyrosine at a position that couples them to the signal-generating proteins Ras and PI3 kinase. Neurotrophin applied at sciatic nerve terminals increases both catalytic activity and phosphorylation state of Trk receptors at distant points within the axons. Trk activation initiated at the nerve terminals propagates through the axon toward the nerve cell body at an initial rate that exceeds that of conventional vesicular transport. However, our data suggest that this rapid signal is nevertheless vesicle-associated. Thus, in mature nerves, activated Trk receptors function as rapid retrograde signal carriers to execute remote responses to target-derived neurotrophins.
    Tipo de documento:
    Referencia
    Referencia del producto:
    06-203

  • Support of trigeminal sensory neurons by nonneuronal p75 neurotrophin receptors. 15126035

    The p75 neurotrophin receptor (p75NTR) binds all four mammalian neurotrophins, including neurotrophin-3 (NT-3) required for the development of select sensory neurons. This study demonstrated that many gustatory and somatosensory neurons of the tongue depend upon p75NTR. Each of thousands of filiform papillae at the front of the tongue as well as each somatosensory prominence at the back of the tongue has a small cluster of p75NTR-positive epithelial cells that is targeted by somatosensory innervation. This expression of p75NTR by epithelial target cells required NT-3 but not adult innervation. NT-3-secreting cells were adjacent to the p75NTR-positive target cells of each somatosensory organ, as demonstrated in NT-3(lacZneo) transgenic mice. In NT-3 null mutant mice, there were few lingual somatosensory neurons. In p75NTR null mutant mice, the lingual somatosensory axons were likewise absent or had deficient terminal arborizations. Cell culture indicated that substrate p75NTR can influence neuronal outgrowth. Specifically, dissociated trigeminal sensory neurons more than doubled their neurite lengths when grown on a lawn of p75NTR-overexpressing fibroblasts. This enhancement of neurite outgrowth by fibroblast p75NTR raises the possibility that epithelial target cell p75NTR may help to promote axonal arborization in vivo. The co-occurrence in p75NTR null mice of a 35% reduction in geniculate ganglion taste neurons and a shortfall of taste buds is consistent with the established role of gustatory innervation in prompting mammalian taste receptor cell differentiation.
    Tipo de documento:
    Referencia
    Referencia del producto:
    07-226
    Nombre del producto:
    Anti-TrkC Antibody

  • Conventional kinesin-I motors participate in the anterograde axonal transport of neurotrophins in the visual system. 17243173

    Retinal ganglion cells (RGCs) anterogradely transport neurotrophins to the midbrain tectum/superior colliculus with significant downstream effects. The molecular mechanism of this type of axonal transport of neurotrophins is not well characterized. We identified kinesin-I proteins as a motor participating in the anterograde axonal movement of vesicular structures containing radiolabeled neurotrophins along the optic nerve. RT-PCR analysis of purified murine RGCs showed that adult RGCs express all known members of the kinesin-I family. After intraocular injection of (125)I-brain-derived neurotrophic factor (BDNF) into the adult mouse or (125)I-neurotrophin-3 (NT-3) into the embryonic chicken eye, radioactivity was efficiently immunoprecipitated from the optic nerve lysates by anti-kinesin heavy chain and anti-kinesin light chain monoclonal antibodies (H2 and L1). Immunoreactivity for the BDNF receptor trkB is also present in the immunoprecipitates obtained by the anti-kinesin-I antibodies. The delivery of the H2 antibody in vivo into the mouse RGCs substantially reduced anterograde axonal transport of (125)I-BDNF. Anterograde transport of BDNF was not diminished in kinesin light chain 1 (KLC1) knockout mice. However, this may be due to redundancy in functions between two different isoforms of KLC present in the RGCs, as it was described previously for kinesin heavy chains (Kanai et al. [ 2000] J Neurosci 20:6374-6384). These data indicate that kinesin-I is a protein motor that participates in the anterograde axonal transport of neurotrophins in the chicken and mouse visual pathways.
    Tipo de documento:
    Referencia
    Referencia del producto:
    Múltiplo