DSCAM localization and function at the mouse cone synapse

Andrade, Gabriel Belem de; Long, Sean P.; Fleming, Harrison; Li, Wei; Fuerst, Peter G.

doi:10.1002/cne.23552

Cited by 21 publications

(26 citation statements)

References 60 publications

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“…From E12.5 through to postnatal ages Dscam is expressed strongly by most, if not all, RGCs (5). Double immunofluorescent staining of cultured P0 retinal ganglion cells with antibodies validated previously against DSCAM (12)(13)(14) and neurofilament confirmed that DSCAM localized to retinal axons, with expression concentrated at the growth cone (Fig. 1A, white arrowhead).…”

Section: Resultssupporting

confidence: 78%

DSCAM promotes axon fasciculation and growth in the developing optic pathway

Bruce

Brown

Smith

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Although many aspects of optic pathway development are beginning to be understood, the mechanisms promoting the growth of retinal ganglion cell (RGC) axons toward visual targets remain largely unknown. Down syndrome cell adhesion molecule (Dscam) is expressed by mouse RGCs shortly after they differentiate at embryonic day 12 and is essential for multiple aspects of postnatal visual system development. Here we show that Dscam is also required during embryonic development for the fasciculation and growth of RGC axons. Dscam is expressed along the developing optic pathway in a pattern consistent with a role in regulating RGC axon outgrowth. In mice carrying spontaneous mutations in Dscam (Dscam), RGC axons pathfind normally, but growth from the chiasm toward their targets is impaired, resulting in a delay in RGC axons reaching the dorsal thalamus compared with that seen in wild-type littermates. Conversely, Dscam gain of function results in exuberant growth into the dorsal thalamus. The growth of ipsilaterally projecting axons is particularly affected. Axon organization in the optic chiasm and tract and RGC growth cone morphologies are also altered in Dscam mutants. In vitro DSCAM promotes RGC axon growth and fasciculation, and can act independently of cell contact. In vitro and in situ DSCAM is required both in the RGC axons and in their environment for the promotion of axon outgrowth, consistent with a homotypic mode of action. These findings identify DSCAM as a permissive signal that promotes the growth and fasciculation of RGC axons, controlling the timing of when RGC axons reach their targets.axon guidance | development | growth cone | optic chiasm | visual system T he developing vertebrate visual system has proven to be one of the most informative model systems for studying axon growth and guidance decision (1). In mice, retinal ganglion cell (RGC) axons grow into the brain from embryonic day (E) 12.5, although mapping within visual targets is not complete until postnatal stages (1). Molecules have been identified that are important for multiple aspects of RGC axon growth and pathfinding, including guidance out of the eye, constraining the general path followed by RGC axons and midline routing at the optic chiasm underlying the establishment of stereovision (1); however, the majority of these molecules induce inhibitory responses in RGC axons. Much less is known about the growth-promoting mechanisms that drive RGC axon extension.Down syndrome cell adhesion molecule 1 (Dscam1) is a homophilic adhesion molecule essential for multiple aspects of neural circuit formation in Drosophila, including axon growth, fasciculation, and pathfinding; dendritic field organization; and synaptic specificity and targeting (2, 3). Although vertebrate Dscam lacks the extensive alternative splicing of fly Dscam1, it is required for many of the same developmental processes, including dendritic arborization and synaptic lamination and refinement (4).Dscam is expressed by mouse RGCs from E12.5 (5) and, through regulation of cell deat...

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Section: Resultssupporting

confidence: 78%

DSCAM promotes axon fasciculation and growth in the developing optic pathway

Bruce

Brown

Smith

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Surprisingly, many of these factors appear to function through repulsion, that is by preventing interactions, rather than promoting them. This list would include DSCAM and sidekick proteins, MEGF proteins, the γ-protocadherin, semaphorins and plexins (de Andrade et al, 2014; Fuerst et al, 2009; Fuerst et al, 2008; Kay et al, 2012; Lefebvre et al, 2012; Matsuoka et al, 2011; Yamagata and Sanes, 2008). While neurexins and neuroligins are required for synaptic pairing, the limited diversity of neuroligins in the mouse retina suggests that other factors are playing a role in promoting adhesion (Ichtchenko et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

“…We have previously characterized the role of the DSCAM at the cone synapse and found that if facilitates organization of several types of bipolar cells (de Andrade et al, 2014). Mammalian Dscams lack the splice diversity of fly Dscams and the role of providing this diversity may be subsumed by the protocadherins in the vertebrate (Sanes and Zipursky, 2010).…”

Section: Discussionmentioning

confidence: 99%

Developmental localization of adhesion and scaffolding proteins at the cone synapse

Nuhn

Fuerst

2014

Gene Expression Patterns

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The cone synapse is a complex signaling hub composed of the cone photoreceptor terminal and the dendrites of bipolar and horizontal cells converging around multiple ribbon synapses. Factors that promote organization of this structure are largely unexplored. In this study we characterize the localization of adhesion and scaffolding proteins that are localized to the cone synapse, including alpha-n-catenin, beta-catenin, gamma-protocadherin, cadherin-8, MAGI2 and CASK. We describe the localization of these proteins during development of the mouse retina and in the adult macaque retina and find that these proteins are concentrated at the cone synapse. The localization of these proteins was then characterized at the cellular and subcellular levels. Alpha-ncatenin, gamma-protocadherin and cadherin-8 were concentrated in the dendrites of bipolar cells that project to the cone synapse but were not detected or stained very dimly in the dendrites of cells projecting to rod synapses. This study adds to our knowledge of cone synapse development by characterizing the developmental localization of these factors and identifies these factors as candidates for functional analysis of cone synapse formation.

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“…Nearest neighbor analysis was performed as previously described using the program winDRP (de Andrade et al, 2014; Keeley and Reese, 2014; Rockhill et al, 2000; Wassle and Riemann, 1978). Soma size was set at 10 μm, with 25 10 μm bins selected for analysis.…”

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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DSCAM localization and function at the mouse cone synapse

Cited by 21 publications

References 60 publications

DSCAM promotes axon fasciculation and growth in the developing optic pathway

DSCAM promotes axon fasciculation and growth in the developing optic pathway

Developmental localization of adhesion and scaffolding proteins at the cone synapse

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

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