DSCAM Promotes Refinement in the Mouse Retina through Cell Death and Restriction of Exploring Dendrites

Li, Shuai; Sukeena, Joshua M.; Simmons, Aaron B.; Hansen, Ethan J.; Nuhn, Renee E.; Samuels, Ivy S.; Fuerst, Peter G.

doi:10.1523/jneurosci.2202-14.2015

Cited by 48 publications

(62 citation statements)

References 75 publications

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“…Bax deficient mice share many phenotypes in common with Dscam LOF mice , including dendrite clumping and a reduction in RGC developmental cell death (Chen et al, 2013; Keeley et al, 2012; Li et al, 2015) (Figure 5 A). Therefore we tested if the Bax null retina phenocopied RGC axon remodeling phenotypes observed in the Dscam mutant retina.…”

Section: Resultsmentioning

confidence: 99%

“…Differential expression of these isoforms permits cell specific identification and avoidance of a given cell's dendrites (Hattori et al, 2007; Hughes et al, 2007). Dscams in the mouse retina have previously been reported to guide dendrite lamination (Li et al, 2015) and are required to prevent ectopic clumping of cell bodies and dendrites in the mouse retina (Fuerst et al, 2009). The prevention of cell and dendrite clumping in the mouse retina occurs within cell types, consistent with the lack of extensive alternative splicing of vertebrate Dscams (Agarwala et al, 2000; Yamakawa et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

“…The Down syndrome cell adhesion molecule (DSCAM) protein is a homophilic cell adhesion molecule (Agarwala et al, 2000; Yamakawa et al, 1998) that also serves as a receptor for the axon guidance molecule netrin (Liu et al, 2009; Ly et al, 2008). The Dscam gene is required for several features of normal retinal development including: developmental cell death (Fuerst et al, 2008), lamination (Yamagata and Sanes, 2008), dendrite-refinement (Li et al, 2015), and to prevent clustering of cell bodies and dendrites (Fuerst et al, 2009). Axons of Dscam mutant RGCs project normally to the optic nerve head (Fuerst et al, 2009), suggesting that alternative netrin receptors guide RGC axons out of the retina (Deiner et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…This creates an experimental test system where cells experience diffusible signals, matrix interactions, and cell to cell contacts on physiological scales. Thus, in this work, we used FGF as a diffusible signal because of its well-established role in signaling transduction critical to eye development (Silies et al, 2010), laminin as ECM because it is ubiquitous in the developing visual system of Drosophila (Singh et al, 2014), and neuronal-glia cell densities that approach physiological numbers based on in vivo spacing and dimensions (Li et al, 2015). …”

Section: Discussionmentioning

confidence: 99%

Controlled microfluidics to examine growth-factor induced migration of neural progenitors in the Drosophila visual system

Beck

Singh

Farooqi

et al. 2016

Journal of Neuroscience Methods

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Background The developing visual system in Drosophila melanogaster provides an excellent model with which to examine the effects of changing microenvironments on neural cell migration via microfluidics, because the combined experimental system enables direct genetic manipulation, in vivo observation, and in vitro imaging of cells, post-embryo. Exogenous signaling from ligands such as fibroblast growth factor (FGF) is well-known to control glia differentiation, cell migration, and axonal wrapping central to vision. New method The current study employs a microfluidic device to examine how controlled concentration gradient fields of FGF are able to regulate the migration of vision-critical glia cells with and without cellular contact with neuronal progenitors. Results Our findings quantitatively illustrate a concentration-gradient dependent chemotaxis toward FGF, and further demonstrate that glia require collective and coordinated neuronal locomotion to achieve directionality, sustain motility, and propagate long cell distances in the visual system. Comparison with existing method(s) Conventional assays are unable to examine concentration- and gradient-dependent migration. Our data illustrate quantitative correlations between ligand concentration/gradient and glial cell distance traveled, independent or in contact with neurons. Conclusions Microfluidic systems in combination with a genetically-amenable experimental system empowers researchers to dissect the signaling pathways that underlie cellular migration during nervous system development. Our findings illustrate the need for coordinated neuron-glia migration in the Drosophila visual system, as only glia within heterogeneous populations exhibited increasing motility along distances that increased with increasing FGF concentration. Such coordinated migration and chemotactic dependence can be manipulated for potential therapeutic avenues for NS repair and/or disease treatment.

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“…Down syndrome cell adhesion molecule (DSCAM) is a neuronal surface receptor involved in the targeting of axon collaterals, dendrite branching and synapse formation during development [154, 216], encoded by an ASD risk gene. Absence of Dscam in Dscam del17 mutant mice results in a transient decrease in the thickness of upper cortical layers.…”

Section: Lessons From Animal Modelsmentioning

confidence: 99%

Autism spectrum disorder: neuropathology and animal models

et al. 2017

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Autism spectrum disorder (ASD) has a major impact on the development and social integration of affected individuals and is the most heritable of psychiatric disorders. An increase in the incidence of ASD cases has prompted a surge in research efforts on the underlying neuropathologic processes. We present an overview of current findings in neuropathology studies of ASD using two investigational approaches, postmortem human brains and ASD animal models, and discuss the overlap, limitations and significance of each. Postmortem examination of ASD brains has revealed global changes including disorganized gray and white matter, increased number of neurons, decreased volume of neuronal soma, and increased neuropil, the last reflecting changes in densities of dendritic spines, cerebral vasculature and glia. Both cortical and non-cortical areas show region-specific abnormalities in neuronal morphology and cytoarchitectural organization, with consistent findings reported from the prefrontal cortex, fusiform gyrus, frontoinsular cortex, cingulate cortex, hippocampus, amygdala, cerebellum and brainstem. The paucity of postmortem human studies linking neuropathology to the underlying etiology has been partly addressed using animal models to explore the impact of genetic and non-genetic factors clinically relevant for the ASD phenotype. Genetically modified models include those based on well-studied monogenic ASD genes (NLGN3, NLGN4, NRXN1, CNTNAP2, SHANK3, MECP2, FMR1, TSC1/2), emerging risk genes (CHD8, SCN2A, SYNGAP1, ARID1B, GRIN2B, DSCAM, TBR1), and copy number variants (15q11-q13 deletion, 15q13.3 microdeletion, 15q11-13 duplication, 16p11.2 deletion and duplication, 22q11.2 deletion). Models of idiopathic ASD include inbred rodent strains that mimic ASD behaviors as well as models developed by environmental interventions such as prenatal exposure to sodium valproate, maternal autoantibodies and maternal immune activation. In addition to replicating some of the neuropathologic features seen in postmortem studies, a common finding in several animal models of ASD is altered density of dendritic spines, with the direction of the change depending on the specific genetic modification, age and brain region. Overall, postmortem neuropathologic studies with larger sample sizes representative of the various ASD risk genes and diverse clinical phenotypes are warranted to clarify putative etiopathogenic pathways further and to promote the emergence of clinically relevant diagnostic and therapeutic tools. In addition, as genetic alterations may render certain individuals more vulnerable to developing the pathological changes at the synapse underlying the behavioral manifestations of ASD, neuropathologic investigation using genetically modified animal models will help to improve our understanding of the disease mechanisms and enhance the development of targeted treatments.

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DSCAM Promotes Refinement in the Mouse Retina through Cell Death and Restriction of Exploring Dendrites

Cited by 48 publications

References 75 publications

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

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

Controlled microfluidics to examine growth-factor induced migration of neural progenitors in the Drosophila visual system

Autism spectrum disorder: neuropathology and animal models

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