Overexpression of Down syndrome cell adhesion molecule impairs precise synaptic targeting

Cvetkovska, Vedrana; Hibbert, Alexa D; Emran, Farida; Chen, Brian E.

doi:10.1038/nn.3396

Cited by 64 publications

(89 citation statements)

References 49 publications

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“…DSCAM also binds the axon guidance molecule netrin and has been shown to play a role in axon path finding in a number of vertebrate species: including chick (Ly et al, 2008), mouse (Liu et al, 2009), zebrafish (Yimlamai et al, 2005) and Xenopus (Morales Diaz, 2014). Dscam dosage has been shown to regulate synaptic organization (Cvetkovska et al, 2013; Kim et al, 2013), but requirements in axon maintenance have not previously been reported.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…For example, ubiquitin-specific peptidase 16 (USP16) or DYRK1A upregulation alters stem cell fate [167][168][169] , which may in turn alter neuronal differentiation. Additionally, overexpression of several chromosome 21 genes (for example, the microRNA gene mir-155 and the protein-coding genes SYNJ1, regulator of calcineurin 1 (RCAN1), intersectin 1 (ITSN1) and DS cell adhesion molecule (DSCAM)) has been implicated in deficits in synaptic structure and function 148,170,171 . These genes may also play a part in AD-DS, perhaps via an effect on APP processing or on cognitive reserve.…”

Section: Neuronal Development and Functionmentioning

confidence: 99%

A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome

et al. 2015

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Down syndrome, which arises in individuals carrying an extra copy of chromosome 21, is associated with a greatly increased risk of early-onset Alzheimer disease. It is thought that this risk Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts is conferred by the presence of three copies of the gene encoding amyloid precursor protein (APP) -an Alzheimer disease risk factor -although the possession of extra copies of other chromosome 21 genes may also play a part. Further study of the mechanisms underlying the development of Alzheimer disease in people with Down syndrome could provide insights into the mechanisms that cause dementia in the general population.Down syndrome (DS) is a complex, highly variable disorder that arises from trisomy of chromosome 21. It was one of the first chromosomal disorders to be identified 1 and occurs with an incidence of approximately 1 in 800 births 2 . Its prevalence within a given population is influenced by infant mortality rates, access to health care, termination rates, average maternal age 3 and life expectancy. Indeed, despite the increased availability of prenatal diagnosis and access to the option of termination, the global prevalence of DS is rising because of improvements in life expectancy: the number of adults with DS aged over 40 years has doubled in northern Europe since 1990 and, in the United Kingdom, one-third of the estimated 40,000 people with DS are thought to be over 40 years of age 4 .DS is the most common form of intellectual disability. In addition to the features that are found in everyone with the disorder, such as the characteristic facial dysmorphology, there are many DS-associated phenotypes that have variable penetrance and severity. For example, approximately 40% of individuals with DS have heart malformations (usually atrioventricular septal defects) 5 . A key feature of DS is a striking propensity to develop early-onset Alzheimer disease (EOAD). Complete trisomy of chromosome 21 universally causes the development of amyloid plaques and neurofibrillary tangles (NFTs), which are typical characteristics of AD brain pathology, by the age of 40, and approximately twothirds of individuals with DS develop dementia by the age of 60 (REFS 6,7). However, rates of dementia do not reach 100%, even in older individuals, suggesting that some individuals with DS are protected from the onset of AD (FIG. 1).All of the features of DS arise because of aberrant dosages of coding and/or non-coding sequences present on chromosome 21. Among these sequences, the gene encoding amyloid precursor protein (APP) is thought to have a key role in the pathology of AD. The additional copy of APP may drive the development of AD in individuals with DS (AD-DS) by increasing the levels of amyloid-β (Aβ), a cleavage product of APP that misfolds and accumulates in the brain in people with AD. Consistent with this hypothesis, individuals with small internal chromosome 21 duplications that result in three copies of APP -a rare familial trait known as duplic...

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“…the molecular recognition of specific markers in targets (Zipursky and Sanes, 2010). Several molecules have been implicated in promoting regional or local specificity between axons and their targets, such as EphA and EphrinA (Cheng et al, 1995;Feldheim et al, 2000), Dscam and Sidekick (Yamagata and Sanes, 2008;Cvetkovska et al, 2013), and Capricious (ShinzaKameda et al, 2006;Kurusu et al, 2008), among others. More recently, Cadherins (Osterhout et al, 2011;Williams et al, 2011) and Teneurins Mosca et al, 2012) have been demonstrated to be crucial in the matching of individual axons with their specific dendritic targets at the level of individual synapses.…”

Section: Similarities Between Axon-opc Interactions During Myelinatiomentioning

confidence: 99%