Neuronal death induced by endogenous extracellular ATP in retinal cholinergic neuron density control

Resta, Valentina; Novelli, Elena; Virgilio, Francesco Di; Galli‐Resta, Lucia

doi:10.1242/dev.01855

Cited by 66 publications

(55 citation statements)

References 55 publications

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“…They also suggest that ATP-mediated neuronal apoptosis occurs through the activation of P2X7 receptors. This idea is supported by other studies showing that activation of these receptors induces the death of specific neuronal populations in the adult or developing mammalian retina [32,34,35].…”

Section: Discussionsupporting

confidence: 65%

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ATP induces the death of developing avian retinal neurons in culture via activation of P2X7 and glutamate receptors

Anccasi

Ornelas

Cossenza

et al. 2012

Purinergic Signalling

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Previous data suggest that nucleotides are important mitogens in the developing retina. Here, the effect of ATP on the death of cultured chick embryo retina cells was investigated. In cultures obtained from retinas of 7-day-old chick embryos (E7) that were cultivated for 2 days (E7C2), both ATP and BzATP induced a ∼30 % decrease in cell viability that was time-and dose-dependent and that could be blocked by 0.2 mM oxidized ATP or 0.3 μM KN-62. An increase in cleaved caspase-3 levels and in the number of TUNELpositive cells was observed when cultures were incubated with 3 mM ATP and immunolabeling for cleaved-caspase 3 was observed over neurons but not over glial cells. ATPdependent cell death was developmentally regulated, the maximal levels being detected by E7C2-3. Nucleotides were able to increase neuronal ethidium bromide and sulforhodamine B uptake in mixed and purified neuronal cultures, an effect that was blocked by the antagonists Brilliant Blue G and oxidized ATP. In contrast, nucleotide-induced cell death was observed only in mixed cultures, but not in purified cultures of neurons or glia. ATP-induced neuronal death was blocked by the glutamatergic antagonists MK801 and DNQX and activation of P2X7 receptors by ATP decreased the uptake of [ These results suggest that ATP induces apoptosis of chick embryo retinal neurons in culture through activation of P2X7 and glutamate ionotropic receptors. Involvement of a P2X7 receptor-mediated inhibition of the glial uptake of glutamate is suggested.

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Section: Discussionsupporting

confidence: 65%

“…In the adult rat retina, prolonged activation of P2X7 induces the death of photoreceptors [32] and of purified ganglion cells in culture [34]. In the retina of newborn rats, activation of these receptors induces the death of cholinergic neurons that contributes to establish the density of these neurons in the adult tissue [35].…”

Section: Introductionmentioning

confidence: 99%

ATP induces the death of developing avian retinal neurons in culture via activation of P2X7 and glutamate receptors

Anccasi

Ornelas

Cossenza

et al. 2012

Purinergic Signalling

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“…As newly generated cholinergic amacrine cells migrate, they exhibit no minimal spacing with their homotypic neighbors, indicating that establishment of mosaic regularity occurs only after these cells arrive and integrate into their emerging mosaics (7). Although these cells are modestly overproduced during development, the regularity of their mosaic is not improved after those extraneous cells die (being Bax independent), nor is the regularity disrupted if these cells are maintained experimentally (20,21). The primary factor in establishing patterning of this mosaic, therefore, is thought to act through homotypic interactions that minimize proximity between like-type cells, driving them apart (2).…”

Section: Discussionmentioning

confidence: 99%

Pituitary tumor-transforming gene 1 regulates the patterning of retinal mosaics

Keeley

Zhou

et al. 2014

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

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Neurons are commonly organized as regular arrays within a structure, and their patterning is achieved by minimizing the proximity between like-type cells, but molecular mechanisms regulating this process have, until recently, been unexplored. We performed a forward genetic screen using recombinant inbred (RI) strains derived from two parental A/J and C57BL/6J mouse strains to identify genomic loci controlling spacing of cholinergic amacrine cells, which is a subclass of retinal interneuron. We found conspicuous variation in mosaic regularity across these strains and mapped a sizeable proportion of that variation to a locus on chromosome 11 that was subsequently validated with a chromosome substitution strain. Using a bioinformatics approach to narrow the list of potential candidate genes, we identified pituitary tumortransforming gene 1 (Pttg1) as the most promising. Expression of Pttg1 was significantly different between the two parental strains and correlated with mosaic regularity across the RI strains. We identified a seven-nucleotide deletion in the Pttg1 promoter in the C57BL/6J mouse strain and confirmed a direct role for this motif in modulating Pttg1 expression. Analysis of Pttg1 KO mice revealed a reduction in the mosaic regularity of cholinergic amacrine cells, as well as horizontal cells, but not in two other retinal cell types. Together, these results implicate Pttg1 in the regulation of homotypic spacing between specific types of retinal neurons. The genetic variant identified creates a binding motif for the transcriptional activator protein 1 complex, which may be instrumental in driving differential expression of downstream processes that participate in neuronal spacing.L ike many other CNS structures, the retina is composed of recurring modular microcircuits. Distinct neuronal populations are each distributed across the tissue and establish stereotypic patterns of connectivity with one another. To ensure a complete functional coverage by these microcircuits, individual neuronal populations are arranged in regular arrays across the entire retina (1). The regularity of these arrays is achieved by the presence of a zone of exclusion surrounding each cell, minimizing proximity between like-type cells, and although several developmental mechanisms, such as selective cell death and tangential migration, have been shown to mediate formation of such exclusion zones (2), the molecular underpinnings of these processes have received little attention. Recently, however, the EGF-like transmembrane receptor Megf10, which is expressed in only two neuronal populations of the retina, has been shown to mediate recognition and repulsion between like-type cells (3). In another retinal neuronal population, the anti-and proapoptotic factors Bcl2 and Bax have been shown to modulate programmed cell death, a process that yields increased regularity of this mosaic (4, 5). Aside from these examples, relatively little is known about the genetic determinants that coordinate these retinal cell biological processes.In the pre...

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“…11). DSCAM-mediated self-recognition may therefore be upstream of cell death in the wild-type retina, whereas non-Dscamexpressing cells may use other mechanisms for spacing 21 .…”

mentioning

confidence: 99%

Neurite arborization and mosaic spacing in the mouse retina require DSCAM

Fuerst

Koizumi

Burgess

2008

Nature

279

345

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To establish functional circuitry, retinal neurons occupy spatial domains by arborizing their processes, which requires the selfavoidance of neurites from an individual cell, and by spacing their cell bodies, which requires positioning the soma and establishing a zone within which other cells of the same type are excluded 1 . The mosaic patterns of distinct cell types form independently and overlap. The cues that direct these processes in the vertebrate retina are not known 2,3 . Here we show that some types of retinal amacrine cells from mice with a spontaneous mutation in Down syndrome cell adhesion molecule (Dscam), a gene encoding an immunoglobulin-superfamily member adhesion molecule 4,5 , have defects in the arborization of processes and in the spacing of cell bodies. In the mutant retina, cells that would normally express Dscam have hyperfasciculated processes, preventing them from creating an orderly arbor. Also, their cell bodies are randomly distributed or pulled into clumps rather than being regularly spaced mosaics. Our results indicate that mouse DSCAM mediates isoneuronal self-avoidance for arborization and heteroneuronal self-avoidance within specific cell types to prevent fasciculation and to preserve mosaic spacing. These functions are analogous to those of Drosophila DSCAM (ref. 6) and DSCAM2 (ref. 7). DSCAM may function similarly in other regions of the mammalian nervous system, and this role may extend to other members of the mammalian Dscam gene family.We have identified a spontaneous mutation in mice that creates a loss-of-function allele of Dscam, the Drosophila homologues of which function in both isoneuronal self-avoidance for dendrite arborization and heteroneuronal self-avoidance for axon tiling [7][8][9][10][11][12] . The recessive mutation arose in the BALB/cByJ genetic background and caused an overt neurological phenotype. Mutant and wild-type mice are indistinguishable at birth, but are severely uncoordinated by postnatal day 3 (P3); as adults, the mutant mice have spontaneous seizures and kyphosis, but are fertile and long-lived (.24 months; see http://www.jax.org/research/media/wild_type.html for video). Through positional cloning (see Methods), a mutation was identified in Dscam. Sequencing of genomic and complementary DNA from affected mice revealed a 38-bp deletion in exon 17, causing a frame shift resulting in ten unique amino acids followed by a premature stop codon (Supplementary Fig. 1). This mutation truncates the protein in the second fibronectin repeat (Fig. 1a). Dscam messenger RNA levels in the brain were reduced by 70% in affected mice, consistent with nonsense-mediated decay (Fig. 1b).

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Neuronal death induced by endogenous extracellular ATP in retinal cholinergic neuron density control

Cited by 66 publications

References 55 publications

ATP induces the death of developing avian retinal neurons in culture via activation of P2X7 and glutamate receptors

ATP induces the death of developing avian retinal neurons in culture via activation of P2X7 and glutamate receptors

Pituitary tumor-transforming gene 1 regulates the patterning of retinal mosaics

Neurite arborization and mosaic spacing in the mouse retina require DSCAM

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