Cell autonomy of DSCAM function in retinal development

Fuerst, Peter G.; Bruce, Freyja; Rounds, Ryan P.; Erskine, Lynda; Burgess, Robert W.

doi:10.1016/j.ydbio.2011.10.028

Cited by 41 publications

(45 citation statements)

References 49 publications

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“…Defects in horizontal-cell dendritic process self-avoidance in PlexA4 -/- and Sema6A -/- retinas result in abnormal dendrite elaboration, and these phenotypes likely affect the formation of appropriate connections with neighboring horizontal cell dendrites and/or cone photoreceptor axon terminals. The horizontal-cell self-avoidance defect we observe is unique in that it is not accompanied by alterations in horizontal-cell mosaic cell body spacing, as is observed in DSCAMs mutants (Fuerst et al, 2008; Fuerst et al, 2009; Fuerst et al, 2011). …”

Section: Discussionsupporting

confidence: 53%

Guidance-Cue Control of Horizontal Cell Morphology, Lamination, and Synapse Formation in the Mammalian Outer Retina

et al. 2012

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In the vertebrate retina, neuronal circuitry required for visual perception is organized within specific laminae. Photoreceptors convey external visual information to bipolar and horizontal cells at triad ribbon synapses established within the outer plexiform layer (OPL), initiating retinal visual processing. However, the molecular mechanisms that organize these three classes of neuronal processes within the OPL, thereby ensuring appropriate ribbon-synapse formation, remain largely unknown. Here we show that mice with null mutations in Sema6A or PlexinA4 (PlexA4) exhibit a pronounced defect in OPL stratification of horizontal-cell axons without any apparent deficits in bipolar-cell dendrite or photoreceptor-axon targeting. Furthermore, these mutant horizontal cells exhibit aberrant dendritic arborization and reduced dendritic self-avoidance within the OPL. Ultrastructural analysis shows that the horizontal-cell contribution to rod-ribbon-synapse formation in PlexA4-/- retinas is disrupted. These findings define molecular components required for outer-retina lamination and ribbon-synapse formation.

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Section: Discussionsupporting

confidence: 53%

Guidance-Cue Control of Horizontal Cell Morphology, Lamination, and Synapse Formation in the Mammalian Outer Retina

et al. 2012

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“…This suggested that mouse Dscams are acting as part of a larger identity code, and do not specify cell type [13]. Conditional deletion of Dscam confirmed that the protein acts to prevent fasciculation by acting within and not between retinal cell types and through homotypic binding, in that the null phenotype is dominant within cell types, that is mutant cells will entangle homotypic wild type cells within the same retina [34]. All of these mechanisms in mouse retina are consistent with DSCAM acting as a homophilic transmembrane cell adhesion molecule.…”

Section: Discussionmentioning

confidence: 98%

A Novel Mouse Dscam Mutation Inhibits Localization and Shedding of DSCAM

Schramm

Harris

et al. 2012

PLoS ONE

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The differential adhesion hypothesis of development states that patterning of organisms, organs and tissues is mediated in large part by expression of cell adhesion molecules. The cues provided by cell adhesion molecules are also hypothesized to facilitate specific connectivity within the nervous system. In this study we characterize a novel mouse mutation in the gene Dscam (Down Syndrome Cell Adhesion Molecule). Vertebrate DSCAM is required for normal development of the central nervous system and has been best characterized in the visual system. In the visual system DSCAM is required for regulation of cell number, mosaic formation, laminar specificity, and refinement of retinal-tectal projections. We have identified a novel mutation in Dscam that results in a single amino acid substitution, R1018P, in the extracellular domain of the DSCAM protein. Mice homozygous for the R1018P mutation develop a subset of defects observed in Dscam null mice. In vitro analysis identified defects in DSCAMR1018P localization to filopodia. We also find that wild type DSCAM protein is constitutively cleaved and shed from transfected cells. This secretion is inhibited by the R1018P mutation. We also characterized a novel splice isoform of Dscam and identified defects in lamination of type 2 and type 6 cone bipolar cells in Dscam mutant mice. The identification and characterization of partial loss of function mutations in genes such as Dscam will be helpful in predicting signs and symptoms that may be observed in human patients with partial loss of DSCAM function.

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“…Dscam del17 , Dscam 2J , Dscam F and Dscam FD mice (truncation, protein null, conditional and germ line-targeted conditional, respectively) were genotyped as previously described (Fuerst et al, 2012; Fuerst et al, 2010; Fuerst et al, 2008). Dscam del17 , Dscam 2J and Dscam FD mice are collectively referred to as Dscam LOF (loss of function) unless otherwise noted.…”

Section: Methodsmentioning

confidence: 99%

Novel axon projection after stress and degeneration in the Dscam mutant retina

Fernandes

Bloomsburg

Miller

et al. 2016

Molecular and Cellular Neuroscience

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The Down syndrome cell adhesion molecule gene (Dscam) is required for normal dendrite patterning and promotes developmental cell death in the mouse retina. Loss-of-function studies indicate that Dscam is required for refinement of retinal ganglion cell (RGC) axons in the lateral geniculate nucleus, and in this study we report and describe a requirement for Dscam in the maintenance of RGC axon projections within the retina. Mouse Dscam loss of function phenotypes related to retinal ganglion cell axon outgrowth and targeting have not been previously reported, despite the abundance of axon phenotypes reported in Drosophila Dscam1 loss and gain of function models. Analysis of the Dscam deficient retina was performed by immunohistochemistry and western blot analysis during postnatal development of the retina. Conditional targeting of Dscam and Jun was performed to identify factors underlying axon-remodeling phenotypes. A subset of RGC axons were observed to project and branch extensively within the Dscam mutant retina after eye opening. Axon remodeling was preceded by histological signs of RGC stress. These included neurofilament accumulation, axon swelling, axon blebbing and activation of JUN, JNK and AKT. Novel and extensive projection of RGC axons within the retina was observed after upregulation of these markers, and novel axon projections were maintained to at least one year of age. Further analysis of retinas in which Dscam was conditionally targeted with Brn3b or Pax6α Cre indicated that axon stress and remodeling could occur in the absence of hydrocephalus, which frequently occurs in Dscam mutant mice. Analysis of mice mutant for the cell death gene Bax, which executes much of Dscam dependent cell death, identified a similar axon misprojection phenotype. Deleting Jun and Dscam resulted in increased axon remodeling compared to Dscam or Bax mutants. Retinal ganglion cells have a very limited capacity to regenerate after damage in the adult retina, compared to the extensive projections made in the embryo. In this study we find that DSCAM and JUN limit ectopic growth of RGC axons, thereby identifying these proteins as targets for promoting axon regeneration and reconnection.

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Cell autonomy of DSCAM function in retinal development

Cited by 41 publications

References 49 publications

Guidance-Cue Control of Horizontal Cell Morphology, Lamination, and Synapse Formation in the Mammalian Outer Retina

Guidance-Cue Control of Horizontal Cell Morphology, Lamination, and Synapse Formation in the Mammalian Outer Retina

A Novel Mouse Dscam Mutation Inhibits Localization and Shedding of DSCAM

Novel axon projection after stress and degeneration in the Dscam mutant retina

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