Extension of long leading processes and neuronal migration in the mammalian brain directed by the chemoattractant netrin-1.
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Long distance cell migration occurs throughout the developing CNS, but the underlying cellular and molecular mechanisms are poorly understood. We show that the directed circumferential migration of basilar pontine neurons from their origin in the neuroepithelium of the dorsal hindbrain to the ventral midline involves the extension of long (>1 mm) leading processes, which marker analyses suggest are molecularly distinct from axons. In vivo analysis of knockout mice implicates the axonal chemoattractant netrin-1, functioning via its receptor Deleted in Colorectal Cancer (DCC), in attracting the leading process to the ventral midline. Direct evidence for this chemoattractant mechanism is provided, using explant cultures and time-lapse analysis in vitro. Our results demonstrate the attraction of migrating neurons in the mammalian brain by an axon guidance molecule and the chemotactic responsiveness of their leading processes. (+info)
Ataxia and abnormal cerebellar microorganization in mice with ablated contactin gene expression.
(34/1624)
Axon guidance and target recognition depend on neuronal cell surface receptors that recognize and elicit selective growth cone responses to guidance cues in the environment. Contactin, a cell adhesion/recognition molecule of the immunoglobulin gene superfamily, regulates axon growth and fasciculation in vitro, but its role in vivo is unknown. To assess its function in the developing nervous system, we have ablated contactin gene expression in mice. Contactin-/- mutants displayed a severe ataxic phenotype consistent with defects in the cerebellum and survived only until postnatal day 18. Analysis of the contactin-/- mutant cerebellum revealed defects in granule cell axon guidance and in dendritic projections from granule and Golgi cells. These results demonstrate that contactin controls axonal and dendritic interactions of cerebellar interneurons and contributes to cerebellar microorganization. (+info)
Proteins of the CNR family are multiple receptors for Reelin.
(35/1624)
Layering and positioning of neurons require Reelin- and Src family-associated mammalian Disabled (mDab1). Cadherin-related neuronal receptor (CNR) genes are expressed in neurons of the cortical layer, but not in Cajal-Retzius cells expressing Reelin. This leads us to hypothesize that CNRs bound to Fyn of the Src family are receptors for Reelin. Herein we confirm the association and colocalization of CNR proteins with Reelin. This binding is blocked by CR-50 antibody against Reelin, as well as by monoclonal antibodies produced against CNRs. Both disturb the signaling pathway from Reelin to mDab1 and the positioning of cortical neurons in vitro. These results strongly suggest that the CNR family proteins are multiple Reelin receptors. In addition, differential conservation of the Reelin-binding domain among terrestrial vertebrates may be pertinent to the diversity or complexity of brains. (+info)
Localization of membrane-associated guanylate kinase (MAGI)-1/BAI-associated protein (BAP) 1 at tight junctions of epithelial cells.
(36/1624)
Membrane-associated guanylate kinase (MAGI)-1/BAI-associated protein (BAP) 1 and Synapse-associated protein (SAP) 97/human Discs-large tumor suppressor gene (hDLG) are ubiquitous isoforms of synaptic scaffolding molecule (S-SCAM) and Postsynaptic density (PSD)-95/SAP90, both of which are implicated in the structures of synapses, respectively. SAP97/hDLG is localized at epithelial junctions and may function as a scaffolding protein, but the subcellular localization or the function of MAGI-1/BAP1 has not been clarified. In intestinal epithelial cells, MAGI-1/BAP1 was localized at tight junctions, whereas SAP97/hDLG was localized diffusely at cell - cell junctions. In Madine Darby canine kidney (MDCK) cells, MAGI-1/BAP1 was colocalized with ZO-1, whereas SAP97/hDLG was colocalized with E-cadherin. In MDCK cells, dominant active and negative mutants of Rac1 small G protein changed the amounts of SAP97/hDLG at cell - cell junctions, but not that of MAGI-1/BAP1. When MDCK cells were switched to a low Ca2+ medium, E-cadherin disappeared from the plasma membrane, and cells were dissociated. The phorbol 12-myristate 13-acetate-treatment after the low Ca2+ switch induced a tight junction-like structure. MAGI-1/BAP1 was recruited with ZO-1 to this structure, but SAP97/hDLG or E-cadherin was not. These findings suggest that MAGI-1/BAP1 is a component of tight junctions of epithelial cells, and that its role is different from that of SAP97/hDLG. (+info)
Ninjurin2, a novel homophilic adhesion molecule, is expressed in mature sensory and enteric neurons and promotes neurite outgrowth.
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A large number of cell adhesion molecules mediate cell-to-cell and cell-to-extracellular matrix interaction during development, differentiation and regeneration of the peripheral nervous system. Here, we report the identification of a novel cell surface adhesion molecule, ninjurin2 (for nerve injury induced protein 2). Ninjurin2 is a homolog of a homophilic cellular adhesion molecule, ninjurin1, that was previously isolated as a gene induced in Schwann cells after nerve injury. Ninjurin1 and 2 share conserved hydrophobic regions for their transmembrane domains; however, they do not contain comparable adhesion motifs nor do they interact with each other. In the peripheral nervous system, ninjurin2 is expressed constitutively in mature sensory and enteric neurons but not in glial cells or in autonomic ganglia. Ninjurin2 is upregulated in Schwann cells surrounding the distal segment of injured nerve with a time course similar to that of ninjurin1, neural CAM, and L1. Ninjurin2 promotes neurite outgrowth from primary cultured dorsal root ganglion neurons, presumably via homophilic cellular interactions. Ninjurin2 is also highly expressed in hematopoietic and lymphatic tissues. Finally, the ninjurin2 gene is located on human chromosome 12p13 in which several disorders of unknown etiology have been mapped, including inflammatory bowel disease and acrocallosal syndrome. (+info)
A reexamination of spreading of position-effect variegation in the white-roughest region of Drosophila melanogaster.
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In Drosophila, heterochromatin causes mosaic silencing of euchromatic genes brought next to it by chromosomal rearrangements. Silencing has been observed to "spread": genes closer to the heterochromatic rearrangement breakpoint are silenced more frequently than genes farther away. We have examined silencing of the white and roughest genes in the variegating rearrangements In(1)w(m4), In(1)w(mMc), and In(1)w(m51b). Eleven stocks bearing these chromosomes differ widely in the strength of silencing of white and roughest. Stock-specific differences in the relative frequencies of inactivation of white and roughest were found that map to the white-roughest region or the adjacent heterochromatin. Most stock-specific differences did not correlate with gross differences in the heterochromatic content of the rearranged chromosomes; however, two stocks, In(1)w(m51b) and In(1)w(mMc), were found to have anomalous additional heterochromatin that may act in trans to suppress variegating alleles. In comparing different stocks, the frequency of silencing of the roughest gene, which is more distant from heterochromatin, does not correlate with the frequency of silencing of the more proximal white gene on the same chromosome, in contradiction to the expectation of models of continuous linear propagation of silencing. We frequently observed rough eye tissue that is pigmented, as though an active white gene is skipped. (+info)
Investigating the function of follicular subpopulations during Drosophila oogenesis through hormone-dependent enhancer-targeted cell ablation.
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Although it is known that the establishment of polarity during Drosophila oogenesis is initiated by signalling from the oocyte to the overlying follicle cells, much less is understood about the role of specific follicular subpopulations. One powerful approach for addressing this question, toxigenic cell ablation of specific subpopulations, has not previously been applicable to studying follicular subpopulations because many of the genes and Gal4 enhancer trap insertions that are expressed in the ovary are also expressed at earlier times in development. To overcome this problem, we have utilized a fusion protein between Gal4 and the human estrogen receptor to achieve hormone-dependent, tissue-specific gene expression of UAS-linked transgenes in flies. We used this system to study the role of the polar subpopulations of follicle cells during oogenesis by expressing within them a modified form of diphtheria toxin that causes cell death. Our results confirmed previous functions ascribed to these cells, and also demonstrated a previously undescribed role for the border cells in facilitating the migration of the anterior Fasciclin III-expressing polar pair cells to the edge of the oocyte. (+info)
The lack of Emx2 causes impairment of Reelin signaling and defects of neuronal migration in the developing cerebral cortex.
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Neocorticogenesis in mice homozygous for an Emx2 null allele is the topic of this article. The development of both main components of neocortex, primordial plexiform layer derivatives and cortical plate, was analyzed, paying special attention to radial migration of neurons forming the cortical plate. The products of the Reelin gene, normally playing a key role in orchestrating radial migration of these neurons, display normal distribution at the beginning of the cortical neuronogenesis but are absent in the neocortical marginal zone of the mutant mice at the time when the cortical plate is laid down. As a consequence, the development of radial glia is impaired, and neurons making up the cortical plate display abnormal migration patterns. In addition, restricted defects along the rostrocaudal and the mediolateral axes are present in the subplate, suggesting an Emx2-specific role in priming the proper development of this layer. (+info)