Cell-intrinsic requirement of Dscam1 isoform diversity for axon collateral formation

He, Haihuai; Kise, Yoshiaki; Izadifar, Azadeh; Urwyler, Olivier; Ayaz, Derya; Parthasarthy, Akhila; Yan, Bing; Erfurth, Maria-Luise; Dascenco, Dan; Schmucker, Dietmar

doi:10.1126/science.1251852

Cited by 61 publications

(88 citation statements)

References 34 publications

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“…In Drosophila Dscam1 mutants, the impaired extension of mechanosensory axons is associated with changes in growth cone morphology. Growth cones of mutant axons are less complex and have abnormally dense and short filopodia compared with WT axons (35). Analysis of growth cone morphology in the optic tracts of E14.5 Dscam del17/del17 mutants and WT littermates revealed a similar loss of growth cone complexity in the mutants (Fig.…”

Section: Morphology Of Rgc Axon Growth Cones Is Altered In Dscam Del1mentioning

confidence: 79%

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: Morphology Of Rgc Axon Growth Cones Is Altered In Dscam Del1mentioning

confidence: 79%

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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“…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). In addition to promoting dendrite organization, roles for Dscam1 in axon development have been described in Drosophila , where Dscam is required for axon targeting (Hummel et al, 2003; Schmucker et al, 2000; Wang et al, 2002) and regulation of axon branching (He et al, 2014). 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).…”

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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“…Random co-expression of multiple Dscam1 isoforms may also serve a cell-intrinsic function. Loss of Dscam1 exon 6 diversity in mechanosensory neurons disrupted growth cone morphologies, while neighboring ''wildtype'' neurons in contact with the mutants were unaffected (He et al, 2014). Thus, it was proposed that a reduction in the Dscam1 isoform pool likely induces increased same-isoform encounters within a cell, causing more homophilic binding and a gain of Dscam1 function that disrupts axon growth and branching.…”

Section: Neurexin Proteinsmentioning

confidence: 98%

Alternative Splicing in the Mammalian Nervous System: Recent Insights into Mechanisms and Functional Roles

Raj

Blencowe

2015

Neuron

404

392

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High-throughput transcriptomic profiling approaches have revealed that alternative splicing (AS) of precursor mRNAs, a fundamental process by which cells expand their transcriptomic diversity, is particularly widespread in the nervous system. AS events detected in the brain are more highly conserved than those detected in other tissues, suggesting that they more often provide conserved functions. Our understanding of the mechanisms and functions of neural AS events has significantly advanced with the coupling of various computational and experimental approaches. These studies indicate that dynamic regulation of AS in the nervous system is critical for modulating protein-protein interactions, transcription networks, and multiple aspects of neuronal development. Furthermore, several underappreciated classes of AS with the aforementioned roles in neuronal cells have emerged from unbiased, global approaches. Collectively, these findings emphasize the importance of characterizing neural AS in order to gain new insight into pathways that may be altered in neurological diseases and disorders.

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Cell-intrinsic requirement of Dscam1 isoform diversity for axon collateral formation

Cited by 61 publications

References 34 publications

DSCAM promotes axon fasciculation and growth in the developing optic pathway

DSCAM promotes axon fasciculation and growth in the developing optic pathway

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

Alternative Splicing in the Mammalian Nervous System: Recent Insights into Mechanisms and Functional Roles

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