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At least 865 records · Page 48Linked to original sources
PubMed1990

Down-regulation of protein kinase C protects cerebellar granule neurons in primary culture from glutamate-induced neuronal death.

Exposing primary cultures of cerebellar granule neurons to 100 nM phorbol 12-myristate 13-acetate (PMA) for 24 hr decreases the Ca2+/phosphatidylserine/diolein-dependent protein kinase C (PKC; ATP:protein phosphotransferase, EC 2.7.1.37) by approximately 90% in the 100,000 x g supernatant and pellet fractions of neuronal culture homogenates. Immunoblot analysis of the homogenates with polyclonal antibodies raised against either the beta-type PKC peptide or total rat brain PKC reveals a virtual loss of 78-kDa PKC immunoreactivity in the supernatant and a marked decrease of PKC immunoreactivity in the pellet. Exposure of the cultures to 50 microM glutamate for 15 min (no Mg2+) induces the translocation of supernatant PKC immunoreactivity to the pellet. Such translocation persists after glutamate withdrawal and is followed by a progressive increase in neuronal death, which begins 2 hr later. Neuronal death approaches completion in about 24 hr. PMA-induced down-regulation of PKC decreases glutamate-elicited neurotoxicity. Yet, the culture exposure to 100 nM PMA fails to decrease the high-affinity binding of [3H]glutamate to neuronal membranes and does not reduce glutamate-induced activation of ionotropic or metabolotropic receptors (assayed as total membrane current measured in whole-cell voltage-clamped neurons, 45Ca2+ uptake in intact monolayers, inositolphospholipid hydrolysis, and transcriptional activation and translation of c-fos mRNA). Moreover, the immediate cell-body swelling and activation of spectrin proteolysis elicited by glutamate remain unchanged. On the other hand, PMA-induced PKC down-regulation reduces any increase in 45Ca2+ uptake or Ca2(+)-dependent proteolysis (measured as spectrin degradation) after glutamate withdrawal. These results support the view that PKC translocation is operative in glutamate-induced destabilization of cytosolic ionized Ca2+ homeostasis and neuronal death.

Animals↗
PubMed1994

Regulation of neuronal Bcl2 protein expression and calcium homeostasis by transforming growth factor type beta confers wide-ranging protection on rat hippocampal neurons.

Excessive activation of glutamate receptors accompanied by Ca2+ overloading is thought to be responsible for the death of neurons in various conditions including stroke and epilepsy. Neurons also die if deprived of important growth factors and trophic influences, conditions sensitive to certain oncogene products such as the Bcl2 protein. We now demonstrate that transforming growth factor type beta (TGF-beta) prevents neuronal Ca2+ overloading of rat hippocampal neurons in response to the glutamatergic agonist N-methyl-D-aspartate or the Ca2+ ionophore 4-Br-A23187 and, in addition, leads to a substantial increase in neuronal Bcl2 protein expression. Parallel cytotoxicity experiments demonstrate that treatment with TGF-beta protects rat hippocampal neurons from death induced by excitotoxicity, trophic factor removal, and oxidative injury. Thus, TGF-beta may protect against a wide range of toxic insults by regulating two factors with great importance for neuronal viability.

Animals↗
PubMed1999

Mammalian ELAV-like neuronal RNA-binding proteins HuB and HuC promote neuronal development in both the central and the peripheral nervous systems.

Hu proteins are mammalian embryonic lethal abnormal visual system (ELAV)-like neuronal RNA-binding proteins that contain three RNA recognition motifs. Although Drosophila ELAV is required for the correct differentiation and survival of neurons, the roles played by the Hu genes in the mammalian nervous system remain largely unknown. To explore the in vivo functions of mouse Hu proteins, we overexpressed them in rat pheochromocytoma PC12 cells, where they induced neuronal phenotype in the absence of nerve growth factor. We have characterized the functions of various forms of mHuB and mHuC bearing point mutations or deletions. Mutants of mHuC that had amino acid exchanges in the RNP1 domain of the first or second RNA recognition motifs (RRMs) lost biologic activity as well as RNA-binding activity. In addition, the mutants containing only the third RRM failed to induce the neuronal phenotype in PC12 cells and inhibited the biologic activity of cotransfected wild-type mHuB and mHuC, thus acting as a dominant-negative form. However, these mutants could not suppress the nerve growth factor-induced differentiation of PC12 cells. Further, we misexpressed wild-type and dominant-negative Hu in E9.5 mouse embryos, by using electroporation into the neural tube at the level of the rhombencephalon. mHuB and mHuC induced the ectopic expression of neuronal markers, whereas the dominant-negative forms of mHuB and mHuC suppressed the differentiation of central nervous system motor neurons. From these results, we suggest that Hu proteins are required for neuronal differentiation in the mammalian nervous system.

Animals↗
PubMed1995

Binding characteristics of ciliary neurotrophic factor to sympathetic neurons and neuronal cell lines.

Ciliary neurotrophic factor (CNTF) is a cytokine whose actions are largely restricted to the nervous system because of the predominant neuronal distribution of its receptor, CNTFR alpha. In this study, we sought to define the binding characteristics of CNTF to cultured sympathetic neurons and cell lines of neuronal origin. We report that 125I-CNTF binds to cultured sympathetic neurons, MAH, PC12, and EW-1 cells via high and low affinity receptors that can be distinguished on the basis of their dissociation constants (KD1 approximately 10(-12) M and KD2 approximately 10(-9) M). Competition experiments showed that the IC50 for rat and human CNTF were, respectively, 65 pM and 5 nM for sympathetic neurons and 75 pM and 1.2 nM for EW-1 cells. Interestingly, leukemia inhibitory factor (LIF) did not compete for CNTF binding even at 100 nM concentration. The binding of 125I-CNTF to sympathetic neurons involved all three components of the CNTF receptor complex, namely CNTFR alpha, LIFR, and gp130, as shown by cross-linking experiments. CNTF and LIF treatments down-regulated CNTF binding to sympathetic neurons and EW-1 cells, suggesting that heterologous ligands can regulate CNTF receptor levels, which may in turn modulate the efficacy of CNTF in vitro and in vivo.

Animals↗
PubMed2000

Persistent activation of ERK contributes to glutamate-induced oxidative toxicity in a neuronal cell line and primary cortical neuron cultures.

Oxidative stress can trigger neuronal cell death and has been implicated in several chronic neurological diseases and in acute neurological injury. Oxidative toxicity can be induced by glutamate treatment in cells that lack ionotrophic glutamate receptors, such as the immortalized HT22 hippocampal cell line and immature primary cortical neurons. Previously, we found that neuroprotective effects of geldanamycin, a benzoquinone ansamycin, in HT22 cells were associated with a down-regulation of c-Raf-1, an upstream activator of the extracellular signal-regulated protein kinases (ERKs). ERK activation, although often attributed strictly to neuronal cell survival and proliferation, can also be associated with neuronal cell death that occurs in response to specific insults. In this report we show that delayed and persistent activation of ERKs is associated with glutamate-induced oxidative toxicity in HT22 cells and immature primary cortical neuron cultures. Furthermore, we find that U0126, a specific inhibitor of the ERK-activating kinase, MEK-1/2, protects both HT22 cells and immature primary cortical neuron cultures from glutamate toxicity. Glutamate-induced ERK activation requires the production of specific arachidonic acid metabolites and appears to be downstream of a burst of reactive oxygen species (ROS) accumulation characteristic of oxidative stress in HT22 cells. However, inhibition of ERK activation reduces glutamate-induced intracellular Ca(2+) accumulation. We hypothesize that the precise kinetics and duration of ERK activation may determine whether downstream targets are mobilized to enhance neuronal cell survival or ensure cellular demise.

Animals↗
PubMed2000

Biochemical interactions of the neuronal pentraxins. Neuronal pentraxin (NP) receptor binds to taipoxin and taipoxin-associated calcium-binding protein 49 via NP1 and NP2.

Neuronal pentraxin 1 (NP1), neuronal pentraxin 2 (NP2), and neuronal pentraxin receptor (NPR) are members of a new family of proteins identified through interaction with a presynaptic snake venom toxin taipoxin. We have proposed that these three neuronal pentraxins represent a novel neuronal uptake pathway that may function during synapse formation and remodeling. We have investigated the mutual interactions of these proteins by characterizing their enrichment on taipoxin affinity columns; by expressing NP1, NP2, and NPR singly and together in Chinese hamster ovary cells; and by generating mice that fail to express NP1. NP1 and NP2 are secreted, exist as higher order multimers (probably pentamers), and interact with taipoxin and taipoxin-associated calcium-binding protein 49 (TCBP49). NPR is expressed on the cell membrane and does not bind taipoxin or TCBP49 by itself, but it can form heteropentamers with NP1 and NP2 that can be released from cell membranes. This is the first demonstration of heteromultimerization of pentraxins and release of a pentraxin complex by proteolysis. These processes are likely to directly effect the localization and function of neuronal pentraxins in neuronal uptake or synapse formation and remodeling.

Animals↗
PubMed2004

Neuron-restrictive silencer factor (NRSF) functions as a repressor in neuronal cells to regulate the mu opioid receptor gene.

The mu opioid receptor (MOR) is expressed in the central nervous system and specific cell lines with varying expression levels perhaps playing important roles. One of the neuronal-specific transcription regulators, neuron-restrictive silencer factor (NRSF), has been shown to repress the expression of neuron-specific genes in non-neuronal cells. However, we showed here that the neuron-restrictive silencer element (NRSE) of MOR functions as a critical regulator to repress the MOR gene expression in specific neuronal cells depending on NRSF expression level. Using co-transfection studies, we showed that the NRSE of the MOR promoter is functional in NRSF-positive cells (NS20Y and HeLa) but not in NRSF-negative cells (PC12). NRSF binds to the NRSE of the MOR gene in a sequence-specific manner confirmed by supershift and chromatin immunoprecipitation assays, respectively. The suppression of NRSF activity with either trichostatin A or a dominant-negative NRSF induced MOR promoter activity and transcription of the MOR gene. When the NRSF was disrupted in NS20Y and HeLa cells using small interfering RNA, the transcription of the endogenous target MOR gene increased significantly. This provides direct evidence the role of NRSF in the cells and also indicates that NRSF expression is regulated by post-translational modification in neuronal NMB cells. Our data suggested that NRSF can function as a repressor of MOR transcription in specific cells, via a mechanism dependent on the MOR NRSE.

Animals↗
PubMed1985

A neuronal cell surface heparan sulfate proteoglycan is required for dorsal root ganglion neuron stimulation of Schwann cell proliferation.

Axons of dorsal root ganglion neurons express on their surfaces one or more proteins which are mitogenic for Schwann cells (Salzer, J., R. P. Bunge, and L. Glaser, 1980, J. Cell Biol., 84:767-778). Incubation of co-cultures of dorsal root ganglion neurons and Schwann cells with 4-methylumbelliferyl-beta-D-xyloside, an inhibitor of proteoglycan biosynthesis, decreases the mitogenic response of the Schwann cell by over 95%. The effect of the beta-D-xyloside has been localized to the neurons; pretreatment of neurons but not of Schwann cells with the inhibitor causes a marked reduction of the mitogenic response. In addition, Schwann cells treated with beta-D-xyloside are still mitogenically responsive to soluble Schwann cell mitogens (cholera toxin and glial growth factor). Neurons treated with heparitinase and membrane vesicles prepared from heparitinase-treated neurons show diminished mitogenicity for Schwann cells, while other proteoglycan lyases have no effect. We conclude that a cell surface heparan sulfate proteoglycan is a component of the Schwann cell mitogen present on the surface of dorsal root ganglion neurons.

Animals↗
PubMed1991

Relationship between neuronal migration and cell-substratum adhesion: laminin and merosin promote olfactory neuronal migration but are anti-adhesive.

Regulation by the extracellular matrix (ECM) of migration, motility, and adhesion of olfactory neurons and their precursors was studied in vitro. Neuronal cells of the embryonic olfactory epithelium (OE), which undergo extensive migration in the central nervous system during normal development, were shown to be highly migratory in culture as well. Migration of OE neuronal cells was strongly dependent on substratum-bound ECM molecules, being specifically stimulated and guided by laminin (or the laminin-related molecule merosin) in preference to fibronectin, type I collagen, or type IV collagen. Motility of OE neuronal cells, examined by time-lapse video microscopy, was high on laminin-containing substrata, but negligible on fibronectin substrata. Quantitative assays of adhesion of OE neuronal cells to substrata treated with different ECM molecules demonstrated no correlation, either positive or negative, between the migratory preferences of cells and the strength of cell-substratum adhesion. Moreover, measurements of cell adhesion to substrata containing combinations of ECM proteins revealed that laminin and merosin are anti-adhesive for OE neuronal cells, i.e., cause these cells to adhere poorly to substrata that would otherwise be strongly adhesive. The evidence suggests that the anti-adhesive effect of laminin is not the result of interactions between laminin and other ECM molecules, but rather an effect of laminin on cells, which alters the way in which cells adhere. Consistent with this view, laminin was found to interfere strongly with the formation of focal contacts by OE neuronal cells.

Animals↗
PubMed2001

Transgenic mice with an expanded CAG repeat controlled by the human AR promoter show polyglutamine nuclear inclusions and neuronal dysfunction without neuronal cell death.

We generated transgenic mice that expressed a highly expanded 239 polyglutamine (polyQ) repeat under the control of the human androgen receptor promoter. These transgenic mice developed progressive neurological phenotypes of muscular weakness and ataxia, small body size and short life-span. PolyQ nuclear inclusions (NIs) were remarkable and widespread but found in selective regions of the central nervous system (CNS) such as the spinal cord, cerebrum and cerebellum as well as in selective peripheral visceral organs. This distribution pattern resembled that of spinal and bulbar muscular atrophy somewhat, but was more widespread. In neuronal tissues, NIs were present in astrocytes as well as neurons. Cytoplasmic and axonal inclusions were not observed. In the CNS regions with abundant NIs, neuronal populations were well-preserved, and neither neuronal cell death, reactive astrogliosis nor microglial invasions were detected. These findings suggest that polyQ alone can induce the neuronal dysfunction that precedes gross neuronal degeneration and provides a clue for investigating molecular mechanisms that underly the pathway to neuronal dysfunction from polyQ expansion.

Animals↗
PubMed2005

Neuron-specific relaxation of Igf2r imprinting is associated with neuron-specific histone modifications and lack of its antisense transcript Air.

The mouse insulin-like growth factor II receptor (Igf2r) gene and its antisense transcript Air are reciprocally imprinted in most tissues, but in the brain, Igf2r is biallelically expressed despite the imprinted Air expression. To investigate the molecular mechanisms of such brain-specific relaxation of Igf2r imprinting, we analyzed its expression and epigenetic modifications in neurons, glial cells and fibroblasts by the use of primary cortical cell cultures. In glial cells and fibroblasts, Igf2r was maternally expressed and Air was paternally expressed, whereas in the primary cultured neurons, Igf2r was biallelically expressed and Air was not expressed. In the differentially methylated region 2 (DMR2), which includes the Air promoter, allele-specific DNA methylation, differential H3 and H4 acetylation and H3K4 and K9 di-methylation were maintained in each cultured cell type. In DMR1, which includes the Igf2r promoter, maternal-allele-specific DNA hypomethylation, histones H3 and H4 acetylation and H3K4 di-methylation were apparent in glial cells and fibroblasts. However, in neurons, biallelic DNA hypomethylation and biallelic histones H3 and H4 acetylation and H3K4 di-methylation were detected. These data indicate that lack of reciprocal imprinting of Igf2r and Air in the brain results from neuron-specific relaxation of Igf2r imprinting associated with neuron-specific histone modifications in DMR1 and lack of Air expression. Our observation of biallelic Igf2r expression with no Air expression in neurons sheds light on the function of Air as a critical effector in Igf2r silencing and suggests that neuron-specific epigenetic modifications related to the lineage determination of neural stem cells play a critical role in controlling imprinting by antisense transcripts.

Animals↗
PubMed1995

Reticulospinal neurones provide monosynaptic glycinergic inhibition of spinal neurones in lamprey.

In lamprey, distinct groups of reticulospinal neurones utilize different neurotransmitters such as glutamate or serotonin. The present study demonstrates that a group of reticulospinal neurones inhibit their target neurones by an action on glycine receptors. Simultaneous intracellular recordings from a reticulospinal neurone and spinal target neurone shows that the former may evoke an IPSP in the latter. These IPSPs are elicited at a constant latency and amplitude, and follow high frequency stimulation (100 Hz). Furthermore, the IPSPs are maintained when the excitatory amino acid synaptic transmission is blocked, suggesting that the effects are not elicited via a powerful disynaptic pathway. These data taken together establish the monosynaptic nature of the pathway. IPSPs elicited from single reticulospinal neurones or from electrical stimulation of the reticular formation are suppressed by administration of strychnine, suggesting that glycine is the neurotransmitter of these inhibitory reticulospinal neurones.

Animals↗
PubMed1997

DNA fragmentation follows delayed neuronal death in CA1 neurons exposed to transient global ischemia in the rat.

Apoptosis is an active, gene-directed process of cell death in which early fragmentation of nuclear DNA precedes morphological changes in the nucleus and, later, in the cytoplasm. In ischemia, biochemical studies have detected oligonucleosomes of apoptosis whereas sequential morphological studies show changes consistent with necrosis rather than apoptosis. To resolve this apparent discrepancy, we subjected rats to 10 minutes of transient forebrain ischemia followed by 1 to 14 days of reperfusion. Parameters evaluated in the CA1 region of the hippocampus included morphology, in situ end labeling (ISEL) of fragmented DNA, and expression of p53. Neurons were indistinguishable from controls at postischemic day 1 but displayed cytoplasmic basophilia or focal condensations at day 2; some neurons were slightly swollen and a few appeared normal. In situ end labeling was absent. At days 3 and 5, approximately 40 to 60% of CA1 neurons had shrunken eosinophilic cytoplasm and pyknotic nuclei, but only half of these were ISEL. By day 14, many of the necrotic neurons had been removed by phagocytes; those remaining retained mild ISEL. Neither p53 protein nor mRNA were identified in control or postischemic brain by in situ hybridization with riboprobes or by northern blot analysis. These results show that DNA fragmentation occurs after the development of delayed neuronal death in CA1 neurons subjected to 10 minutes of global ischemia. They suggest that mechanisms other than apoptosis may mediate the irreversible changes in the CA1 neurons in this model.

Animals↗
PubMed1979

Autonomic neurons affected by lipid storage in the spinal cord in Fabry's disease: distribution of autonomic neurons in the sacral cord.

In five patients with Fabry's disease, the distribution of neurons in the spinal cord affected by lipid storage was investigated. Neurons ballooned by lipid storage were located mainly in the thoracolumbar and mid-sacral regions. In the former, they were located exclusively in the intermediolateral nucleus from the first thoracic (or eighth cervical) through the first or second lumbar segments. In the mid-sacral region they were located not only in the intermediolateral nucleus but also in the intermedioventral (Onuf's) nucleus and in the intermediate region of the ventral horn. The affected neurons in the sacral cord are also assumed to be autonomic neurons judging from the selective involvement of known autonomic neurons in the thoracolumbar segments. Based on the distribution of these neurons, it is concluded that autonomic neurons in the human sacral cord from a cell column which differs topographically from that in the thoracolumbar segments. The cell column begins rostrally at the ventral margin of the ventral horn in the second sacral segment as Onuf's nucleus and extends caudally in a dorsolateral direction along the intermediate region to the intermediolateral nucleus in the fourth sacral segment, which forms the caudal part of the cell column.

Adult↗
PubMed2005

Neuronal norepinephrine responses of the rostral ventrolateral medulla and nucleus tractus solitarius neurons distinguish the I1- from the alpha2-receptor-mediated hypotension in conscious SHRs.

We tested the hypothesis that the I1 receptor mediates the reduction in rostral ventrolateral medulla (RVLM) neuronal norepinephrine (NE; index of sympathetic activity) that leads to hypotension independent of other brainstem areas or the alpha2-adrenergic receptor. To this end, we developed a model that permitted measurement of real-time changes in neuronal NE in the RVLM or nucleus tractus solitarius (NTS) along with blood pressure and heart rate in the conscious SHR in response to localized microinjections of selective I1 (rilmenidine) or alpha2-adrenergic (alpha-methylnorepinephrine; alpha-MNE) agonist versus the mixed I1/alpha2 agonist clonidine. To further support the hypothesis, we investigated the effects of localized selective alpha2- (SK&F86466) or I1 (efaroxan) blockade on the reductions in neuronal NE and blood pressure elicited by intra-RVLM rilmenidine. In the latter experiment, changes in RVLM neuronal c-Fos (another marker of sympathetic neural activity) were also investigated. Intra-RVLM rilmenidine (40 nmol) or clonidine (1 nmol) similarly reduced RVLM NE and blood pressure; these responses were approximately 2-fold greater than those elicited by the pure alpha2-adrenergic agonist alpha-MNE (10 nmol). By contrast, intra-NTS rilmenidine or clonidine had no effect on NTS NE or blood pressure versus significant reductions in both parameters by alpha-MNE. Intra-RVLM rilmenidine decreased c-Fos expression, and these responses were abolished by efaroxan but not by SK&F 86466. These findings suggest: (1) in the RVLM, I1-receptor signaling suppresses cardiovascular neuron activity, which leads to lowering of blood pressure; (2) although the alpha2-adrenergic receptor in the RVLM serves a similar role, it does not exert a tonic neuronal inhibitory effect and is not essential, as a downstream signaling entity, for the I1-evoked neurobiological effects in the brainstem. The potential confounding effects of anesthetics on the I1 and/or alpha2 receptor-mediated neuronal and cardiovascular responses were circumvented in the present study.

Adrenergic alpha-2 Receptor Agonists↗
PubMed1994

Immunocytochemical evidence for oestrogen receptors within GABA neurones located in the perinuclear zone of the supraoptic nucleus and GABAA receptor beta 2/beta 3 subunits on supraoptic oxytocin neurones.

The mechanisms by which oestrogen modulates the biosynthetic and secretory activity of magnocellular oxytocin neurones are poorly understood. Using an antibody directed against the oestrogen receptor (ER), the distribution of ER-immunoreactive (-IR) cells in relation to the supraoptic nucleus (SON) was examined. Although no ER-IR cells were detected within the SON, a small population of immunoreactive cells separate from those in the preoptic area was identified in the perinuclear zone of the SON. Double-labelling experiments with an antibody specific for glutamic acid decarboxylase (GAD), the neuronal enzyme producing gamma aminobutyric acid (GABA), revealed that approximately 60% of perinuclear zone ER-IR cells contained GAD. A further set of immunocytochemistry experiments using an antibody raised against the beta 2 and beta 3 sub-units of the GABAA receptor revealed immunoreactivity in the SON. Double-labelling experiments demonstrated that both oxytocin-IR and non-oxytocin-IR neurones in the SON were immunoreactive for beta 2 and/or beta 3 sub-units of the GABAA receptor. These studies have identified ERs within a GABAergic neural population in the perinuclear zone of the SON and shown that magnocellular oxytocin neurones in the SON possess GABAA receptors comprised of beta 2 and/or beta 3 sub-units. In conjunction with previous evidence that the perinuclear zone GABA neurones are an important source of GABA terminals in the SON, these results provide a morphological basis for the hypothesis that perinuclear zone GABA neurones may be part of a steroid-sensitive neural circuitry transmitting oestrogen input to oxytocin neurones in the SON.

Animals↗
PubMed1997

Neuronal cell nuclear factor--a nuclear receptor possibly involved in the control of neurogenesis and neuronal differentiation.

We have cloned from a cDNA library of neuronal derivatives of retinoic-acid-induced embryonic carcinoma cells a nuclear receptor that may be involved in the control of late neurogenesis and early neuronal differentiation. The receptor which is practically identical in sequence with germ cell nuclear factor, has been designated neuronal cell nuclear factor (NCNF). NCNF is exclusively expressed in the neuronal derivatives of PCC7-Mz1 cells, with the expression beginning within hours of exposure to retinoic acid. In the developing mouse brain, NCNF is expressed in the marginal zones of the neuroepithelium which are known to contain young postmitotic neurons. NCNF binds to the DR0 sequence thereby silencing transcription. Because NCNF does not recognize hormone response elements of other nuclear receptors tested and does not heterodimerize with these, it probably binds exclusively as a homodimer. NCNF may induce neuronal differentiation by repressing the activity of genes that permit cell fates other than the neuronal one.

Animals↗
PubMed2006

Defects in tangential neuronal migration of pontine nuclei neurons in the Largemyd mouse are associated with stalled migration in the ventrolateral hindbrain.

The LARGE gene encodes a putative glycosyltransferase that is required for normal glycosylation of dystroglycan, and defects in LARGE can cause abnormal neuronal migration in congenital muscular dystrophy (CMD). Previous studies have focused on radial migration, which is disrupted at least in part due to breaks in the basal lamina. Through analysis of precerebellar nuclei development in the Large(myd) mouse hindbrain, we show that tangential migration of a subgroup of hindbrain neurons may also be disrupted. Within the precerebellar nuclei, the pontine nuclei (PN) are severely disrupted, whereas the inferior olive (IO), external cuneate nuclei (ECN) and lateral reticular nuclei (LRN) appear unaffected. Large and dystroglycan are widely expressed in the hindbrain, including in the pontine neurons migrating in the anterior extramural migratory stream (AES). BrdU labeling and immunohistochemical studies suggest normal numbers of neurons begin their journey towards the ventral midline in the AES in the Large(myd) mouse. However, migration stalls and PN neurons fail to reach the midline, surviving as ectopic clusters of cells located under the pial surface dorsally and laterally to where they normally would finish their migration near the ventral midline. Stalling of PN neurons at this location is also observed in other migration disorders in mice. These observations suggest that glycan-dependent dystroglycan interactions are required for PN neurons to correctly respond to signals at this important migrational checkpoint.

Amino Acids↗