Development and diversification of retinal amacrine interneurons at single cell resolution

Cherry, Timothy J.; Trimarchi, Jeffrey M.; Stadler, Michael; Cepko, Constance L.

doi:10.1073/pnas.0903264106

Cited by 115 publications

(154 citation statements)

References 24 publications

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“…For example, recent studies have shown that amacrine subtypes arise at distinct times, as predicted by the competence model (38,43), and that further distinctions among them may result from postmitotic fate choices (44). Similarly, analysis of clones containing late-born retinal cell types (rods, amacrines, bipolars, and Müller glia) indicates that stochastic mechanisms acting on a homogeneous population of progenitors can account for the much of the diversity observed (1,45).…”

Section: Discussionmentioning

confidence: 99%

Direction-selective retinal ganglion cells arise from molecularly specified multipotential progenitors

Huerta

Kim

Voinescu

et al. 2012

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

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Single progenitors can give rise to any and all of the main retinal cell types: photoreceptors, interneurons (horizontal, bipolar, and amacrine cells), retinal ganglion cells (RGCs), and glia. Many of these types are divisible into multiple functionally, structurally, and molecularly distinct subtypes (e.g., ∼25 for RGCs). It remains unknown when and how progenitors become committed to generate such subtypes. Here, we determine the origin of RGCs that respond selectively to vertical motion and express cadherin 6 (cdh6). Using Cre recombinase-based lineage tracing, we show that these RGCs arise from progenitors that themselves express cdh6. These progenitors are capable of generating all major retinal cell types, but the RGCs they generate are predominantly of the single direction-selective subtype. In contrast, cdh6-positive progenitors retain the ability to generate multiple subtypes of amacrine and bipolar cells. Our results demonstrate that type and subtype specification are regulated in different ways and suggest that multipotential but fate-restricted progenitors contribute to subtype specification in retina.

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Section: Discussionmentioning

confidence: 99%

Direction-selective retinal ganglion cells arise from molecularly specified multipotential progenitors

Huerta

Kim

Voinescu

et al. 2012

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

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“…The single cell expression profiles have revealed considerable heterogeneity in gene expression in amacrine cells 4 , where it was expected, and in Müller glia cells, where it was unexpected 5 . While an examination of the single amacrine cell data revealed more than 450 genes that were expressed in amacrine cells and excluded from other retinal cell types, none of these genes were expressed in all the amacrine cells 4 .…”

Section: Discussionmentioning

confidence: 99%

“…While an examination of the single amacrine cell data revealed more than 450 genes that were expressed in amacrine cells and excluded from other retinal cell types, none of these genes were expressed in all the amacrine cells 4 . These results most likely arise from the fact that the amacrine cell class is extremely diverse and the underlying heterogeneity is a reflection of the distinct functions of these cells.…”

Section: Discussionmentioning

confidence: 99%

“…Since the retina is such a mixture of cell types, microarray and serial analysis of gene expression (SAGE) based studies [17][18][19] that relied on the homogenization of the entire retina are unable to uncover markers genes expressed in rare subtypes and unable to resolve dynamic gene expression differences between cell types, especially during development. To begin to understand the complexity of different cell types both in the adult retina and during retinal development, the single cell gene expression profiles of~200 individual cells from many different time points have been analyzed [2][3][4][5]8 . The resulting data has provided a host of new markers for individual cell types and provided a window into important transitions in developmental time that were previously unappreciated.…”

Section: Discussionmentioning

confidence: 99%

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Single-cell Profiling of Developing and Mature Retinal Neurons

Goetz

Trimarchi

2012

JoVE

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Highly specialized, but exceedingly small populations of cells play important roles in many tissues. The identification of cell-type specific markers and gene expression programs for extremely rare cell subsets has been a challenge using standard whole-tissue approaches. Gene expression profiling of individual cells allows for unprecedented access to cell types that comprise only a small percentage of the total tissue 1-7 . In addition, this technique can be used to examine the gene expression programs that are transiently expressed in small numbers of cells during dynamic developmental transitions 8 .This issue of cellular diversity arises repeatedly in the central nervous system (CNS) where neuronal connections can occur between quite diverse cells 9 . The exact number of distinct cell types is not precisely known, but it has been estimated that there may be as many as 1000 different types in the cortex itself 10 . The function(s) of complex neural circuits may rely on some of the rare neuronal types and the genes they express. By identifying new markers and helping to molecularly classify different neurons, the single-cell approach is particularly useful in the analysis of cell types in the nervous system. It may also help to elucidate mechanisms of neural development by identifying differentially expressed genes and gene pathways during early stages of neuronal progenitor development.As a simple, easily accessed tissue with considerable neuronal diversity, the vertebrate retina is an excellent model system for studying the processes of cellular development, neuronal differentiation and neuronal diversification. However, as in other parts of the CNS, this cellular diversity can present a problem for determining the genetic pathways that drive retinal progenitors to adopt a specific cell fate, especially given that rod photoreceptors make up the majority of the total retinal cell population 11 . Here we report a method for the identification of the transcripts expressed in single retinal cells (Figure 1). The single-cell profiling technique allows for the assessment of the amount of heterogeneity present within different cellular populations of the retina 2,4,5,12 . In addition, this method has revealed a host of new candidate genes that may play role(s) in the cell fate decision-making processes that occur in subsets of retinal progenitor cells 8 . With some simple adjustments to the protocol, this technique can be utilized for many different tissues and cell types.

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“…1A and Dataset S1). These cells were analyzed previously (18,(28)(29)(30)(31) and classified as RPCs, amacrine cells (ACs), bipolar cells (BPs), photoreceptors (PRs), and Müller glia (MG). Olig2 was present at a signal level of >1,000 in a small subset of 45 RPCs, but in none of the postmitotic retinal ganglion cells (RGCs), ACs, PRs, BPs and MG.…”

Section: Olig2 Expression In Developing Retina During Embryonic and Pmentioning

confidence: 99%

Transcription factor Olig2 defines subpopulations of retinal progenitor cells biased toward specific cell fates

Hafler

Surzenko

Beier

et al. 2012

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

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138

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Previous lineage analyses have shown that retinal progenitor cells (RPCs) are multipotent throughout development, and expressionprofiling studies have shown a great deal of molecular heterogeneity among RPCs. To determine if the molecular heterogeneity predicts that an RPC will produce particular types of progeny, clonal lineage analysis was used to investigate the progeny of a subset of RPCs, those that express the basic helix-loop-helix transcription factor, Olig2. The embryonic Olig2 + RPCs underwent terminal divisions, producing small clones with primarily two of the five cell types being made by the pool of RPCs at that time. The later, postnatal Olig2 + RPCs also made terminal divisions, which were biased toward production of rod photoreceptors and amacrine cell interneurons. These data indicate that the multipotent progenitor pool is made up of distinctive types of RPCs, which have biases toward producing subsets of retinal neurons in a terminal division, with the types of neurons produced varying over time. This strategy is similar to that of the developing Drosophila melanogaster ventral nerve cord, with the Olig2 + cells behaving as ganglion mother cells.neural progenitors | neural development | oligodendrocyte transcription factor 2

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Development and diversification of retinal amacrine interneurons at single cell resolution

Cited by 115 publications

References 24 publications

Direction-selective retinal ganglion cells arise from molecularly specified multipotential progenitors

Direction-selective retinal ganglion cells arise from molecularly specified multipotential progenitors

Single-cell Profiling of Developing and Mature Retinal Neurons

Transcription factor Olig2 defines subpopulations of retinal progenitor cells biased toward specific cell fates

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