The Down Syndrome Critical Region Regulates Retinogeniculate Refinement

Blank, Martina; Fuerst, Peter G.; Stevens, Beth; Nouri, Navid; Kirkby, Lowry A.; Warrier, Deepti R; Barres, Ben A.; Feller, Marla B.; Huberman, Andrew D.; Burgess, Robert W.; Garner, Craig C.

doi:10.1523/jneurosci.6015-10.2011

Cited by 49 publications

(52 citation statements)

References 73 publications

(122 reference statements)

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“…2 D and F) and ultimately reached their targets (Fig. S9) (33). These findings are consistent with DSCAM providing permissive, but not guidance, signals that promote extension of RGC axons from, but not toward, the optic chiasm.…”

Section: Dscam Issupporting

confidence: 81%

“…By modulating the timing at which RGC axons reach brain targets, DSCAM may contribute to the specificity of brain wiring patterns. Consistent with this idea, Dscam gain-and loss-of-function mutants display defects in the eye-specific segregation or RGC axons in the lateral geniculate nucleus (33). Axon overgrowth defects associated with Dscam overexpression also have been demonstrated in fragile-X syndrome (42).…”

Section: Dscam Is Required In Both Rgc Exons and Their Environment Formentioning

confidence: 64%

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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: Dscam Issupporting

confidence: 81%

Section: Dscam Is Required In Both Rgc Exons and Their Environment Formentioning

confidence: 64%

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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“…Their results suggested that an increase in DSCAM dosage results in more repulsion, while a decrease in DSCAM dosage results in insufficient repulsion (Blank et al, 2011) ) and control flies.…”

Section: Dscam2 Gene Dosage Affects the Optomotor Responsementioning

confidence: 99%

“…Studies in a mouse model for Down syndrome demonstrated circuit refinement in the eye was DSCAM dosage dependent (Blank et al, 2011). Their results suggested that an increase in DSCAM dosage results in more repulsion, while a decrease in DSCAM dosage results in insufficient repulsion (Blank et al, 2011) ) and control flies.…”

Section: Dscam2 Gene Dosage Affects the Optomotor Responsementioning

confidence: 99%

“…A DSCAM dosage-dependent effect on eye circuit refinement was found in in a mouse model for Down syndrome (Blank et al, 2011). Considering that mouse DSCAM and Drosophila Dscam2 share conserved functions, it was questioned whether the amount of repulsive interactions in the eye is Dscam2 dosage dependent.…”

Section: One Copy Of Dscam2 Is Sufficient To Rescue Most Optomotor Phmentioning

confidence: 99%

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Analysing visual behaviour in Drosophila Dscam2 mutants using optimised optomotor and operant control assays

Bosch¹

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The patterns of synaptic connections between neurons in the brain are key determinants of behaviour, but how specific neural circuits lead to distinct behaviours is largely unknown. Cell recognition molecules that mediate interactions between neurons play a crucial role in establishing synaptic connections. Down Syndrome Cell Adhesion Molecule 2 (Dscam2) is required for establishing modularity in the visual system. Dscam2 null flies have a disorganized visual system, lack boundaries between neighbouring modules in the optic lobe and exhibit changes in the postsynaptic composition of photoreceptor synapses. The behavioural consequences of these wiring defects have not been explored previously. In this thesis, I begin to dissect how these changes in neural circuitry affect visual system behaviours such as the optomotor response, object-orientation preference, and attention-like object-tracking. In order to do so, a population and single tethered-fly assay have been optimized and used to explore motion perception by assessing the visual response to a wide range of psychophysical parameters of black/green moving gratings. In addition, a single tethered-fly virtual reality assay has been set-up and used to explore orientation preference and attention-like tracking.Through the population and single tethered-fly optomotor assays, it is shown that Dscam2 null flies can track motion but that their response is opposite to control flies under defined experimental conditions.Through the single tethered-fly virtual reality assay, it is shown that Dscam2 null flies anti-fixate on a dark bar, again the opposite behaviour to control flies. Responses to a light bar are in contrast, the same as controls. It is shown that this anti-fixation is bar width dependent. Together these results demonstrate that the disrupted visual system of the Dscam2 null flies can dramatically change the perception of specific visual cues and modify behaviour. Lastly, other perturbations of Dscam2 were studied such as Dscam2 single isoform and Dscam2 trisomic flies. Dscam2B single isoform flies displayed some motion detection phenotypes. In addition, they were not responding to either a dark or light bar in the tethered virtual reality assay. Dscam2 trisomic flies were able to detect gratings with different spatial and temporal frequencies but had a change in orientation behaviour as they displayed fixation behaviour to both a dark and a light bar. The results provide a foundation for understanding how brain miswiring can lead to changes in behaviour.iii In chapter 1, I outline the background information to provide context for the experiments and overall research aim. In chapter 2, I contrast a population and single fly assay to explore motion detection in Drosophila.In chapter 3, I present a new single fly virtual reality assay which goes beyond simple visual reflexes by measuring object-orientation preferences and attention-like tracking. In chapter 4, I test motion detection in Dscam2 null flies. In chapter 5, I test object-orientation prefe...

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Emerging data on the use of anti‐tumor necrosis factor‐alpha medications in pregnancy

Chambers

Johnson

2012

Birth Defects Research

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Anti-tumor necrosis factor (TNF) α medications are used for the treatment of a number of autoimmune diseases. Evaluation of pregnancy safety for these medications is complicated by the contribution of the underlying maternal disease to adverse pregnancy outcomes, such as preterm delivery and reduced birth weight. Placental transport of these medications is thought to be minimal in the first trimester, thereby providing some reassurance regarding theoretical risks for congenital malformations. Available human exposure data are sparse; however, to date there has been no convincing evidence to support an increased risk for a specific pattern of major congenital malformations with any of the drugs in this group for which some data is currently available. As a result of the improvement of symptoms during pregnancy in some women with autoimmune diseases, it may be possible to discontinue treatment before or shortly after conception. However, in some cases the benefits of treatment and concerns for disease flares in pregnancy have warranted continued treatment during pregnancy. Because of the relatively long half-life of these medications, and theoretical concerns for immune compromise of the infant following exposure in the latter two trimesters, some clinicians recommend discontinuation of treatment in the third trimester to avoid potentially prolonged infant exposure in the postpartum period. Currently ongoing controlled cohort studies for some of the TNF blocker medications will help to provide more definitive answers for clinicians and patients.

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The Down Syndrome Critical Region Regulates Retinogeniculate Refinement

Cited by 49 publications

References 73 publications

DSCAM promotes axon fasciculation and growth in the developing optic pathway

DSCAM promotes axon fasciculation and growth in the developing optic pathway

Analysing visual behaviour in Drosophila Dscam2 mutants using optimised optomotor and operant control assays

Emerging data on the use of anti‐tumor necrosis factor‐alpha medications in pregnancy

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