Determinants of the exclusion zone in dopaminergic amacrine cell mosaics

Raven, Mary A.; Eglen, Stephen J.; Ohab, John; Reese, Benjamin E.

doi:10.1002/cne.10693

Cited by 63 publications

(100 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…One distinguishing feature of the VGluT3 + amacrine cell and type 2 bipolar cell populations is that each undergoes abundant overproduction during development that is subsequently pared down through Bax-mediated apoptosis, producing a mosaic with little more regularity (if any) relative to a random distribution of cells. The same has been shown for dopaminergic amacrine cells, a cell type that does not evidence tangential dispersion during development (17), but rather undergoes substantial Bax-mediated cell death (22), transforming a random distribution of cells into one with a marginally more regular distribution (4). In contrast, cholinergic amacrine cells and horizontal cells do not use selective cell death as a mechanism to increase mosaic regularity during development while both disperse tangentially via Megf-mediated homotypic interactions in the process of establishing their regularity (6,23,24).…”

Section: Discussionmentioning

confidence: 54%

“…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.…”

mentioning

confidence: 99%

See 1 more Smart Citation

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

Keeley

Zhou

et al. 2014

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

Self Cite

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionmentioning

confidence: 54%

mentioning

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.

Self Cite

View full text Add to dashboard Cite

show abstract

“…This orderly arrangement of neurons of the same type is thought to ensure an even sampling of the visual field. Previous studies have shown that lateral cell displacement plays an important role in the formation of retinal mosaics (Galli-Resta et al, 1997;Reese and Galli-Resta, 2002;Reese et al, 1995), but simulation experiments (Jeyarasasingam et al, 1998) and studies of retinal mosaics in death-suppressing transgenic mice (Raven et al, 2003) strongly suggested that cell death also participates in this process. The present study provides direct evidence of a death control mechanism contributing to regular cell spacing and density in a neural population.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2005

View full text Add to dashboard Cite

The precise assembly of neuronal circuits requires that the correct number of pre- and postsynaptic neurons form synaptic connections. Neuronal cell number is thus tightly controlled by cell death during development. Investigating the regulation of cell number in the retina we found an ATP gated mechanism of neuronal death control. By degrading endogenous extracellular ATP or blocking the P2X7 ATP receptors we found that endogenous extracellular ATP triggers the death of retinal cholinergic neurons during normal development. ATP-induced death eliminates cholinergic cells too close to one another, thereby controlling the total number, the local density and the regular spacing of these neurons.

show abstract

“…In contrast, the densities of the ChAT-positive (starburst) and DAB1-positive (AII) cells were slightly decreased. Dopaminergic amacrine cells rely in part on cell death to sculpt their mosaic pattern 20 . We saw decreased TdTmediated dUTP nick end labelling (TUNEL)-positive cells in the developing Dscam 2/2 retina, but saw no change in the number of proliferating cells ( Supplementary Fig.…”

mentioning

confidence: 99%

Neurite arborization and mosaic spacing in the mouse retina require DSCAM

Fuerst

Koizumi

Burgess

2008

Nature

278

345

View full text Add to dashboard Cite

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).

show abstract

Determinants of the exclusion zone in dopaminergic amacrine cell mosaics

Cited by 63 publications

References 56 publications

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

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

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

Neurite arborization and mosaic spacing in the mouse retina require DSCAM

Contact Info

Product

Resources

About