Glucagon-Expressing Neurons within the Retina Regulate the Proliferation of Neural Progenitors in the Circumferential Marginal Zone of the Avian Eye

Fischer, Andy J.; Omar, Ghezal; Walton, Nathaniel A.; Verrill, Thomas; Unson, Cecilia G.

doi:10.1523/jneurosci.3247-05.2005

Cited by 42 publications

(61 citation statements)

References 41 publications

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“…Under normal conditions, the progenitors in the CMZ are relatively quiescent, but can be stimulated to proliferate by intraocular injections of insulin, IGF-I, EGF or Shh, and by increasing rates of ocular growth via form-deprivation [10,14,16,26,32]. Conversely, the proliferation of progenitors can be suppressed by intraocular injections of glucagon or glucagon-like peptide 1 [13]. The quiescent state of the postnatal CMZ may, in part, result from glucagon-mediated inhibitory input from a unique type of retinal neuron that has been termed "bullwhip cell" [13,18].…”

Section: Introductionmentioning

confidence: 99%

“…Conversely, the proliferation of progenitors can be suppressed by intraocular injections of glucagon or glucagon-like peptide 1 [13]. The quiescent state of the postnatal CMZ may, in part, result from glucagon-mediated inhibitory input from a unique type of retinal neuron that has been termed "bullwhip cell" [13,18]. Furthermore, under normal conditions, the progenitors in the postnatal avian CMZ do not generate photoreceptors [14], and do not produce ganglion cells unless stimulated by the combination of insulin and FGF2 [8].…”

Section: Introductionmentioning

confidence: 99%

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Patterning of the circumferential marginal zone of progenitors in the chicken retina

2008

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A circumferential marginal zone (CMZ) of retinal progenitors has been identified in most vertebrate classes, with the exception of mammals. Little is known about the formation of the CMZ during late stages of embryonic retinal histogenesis. Thus, the purpose of this study was to characterize the formation and patterning of the CMZ in the embryonic chicken retina. We identified progenitors by assaying for the expression of proliferating cell nuclear antigen (PCNA), N-cadherin and the nestinrelated filament transitin, and newly generated cells by using BrdU-birthdating. We found that there is a gradual spatial restriction of progenitors into a discreet CMZ during late stages of embryonic development between E16 and hatching, at about E21. In addition, we found that retinal neurons remain immature for prolonged periods of time in far peripheral regions of the retina. Early markers of neuronal differentiation (such as HuD, calretinin and visinin) are expressed by neurons that are found directly adjacent to the CMZ. By contrast, genes that are expressed with a delay (7-10 days; PKC, calbindin, red/green opsin) after terminal mitosis in the central retina are not expressed until as much as 30 days after terminal mitosis in the far peripheral retina. We conclude that the CMZ is gradually formed during late stages of embryonic development and that the neurons that are generated by late-stage CMZ progenitors differentiate much more slowly than neurons generated during early stages of retinal development. We propose that the microenvironment within the far peripheral retina at late stages of development permits the maintenance of a zone of progenitors and slows the differentiation of neurons.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Patterning of the circumferential marginal zone of progenitors in the chicken retina

2008

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“…Indeed, there is a massive accumulation of glucagon-immunoreactive neurites clustered in the CMZ. 17 Further, we found that intraocular injections of glucagon peptide inhibits the proliferation of CMZ progenitors, and inhibition of the glucagon receptor increases the proliferation of CMZ progenitors. 17 The cells that produce the terminals that ramify in the CMZ were revealed to be unique types of cells that are distinct from the GACs.…”

Section: Stem Cells Within the Retinal Margin And Nonpigmented Epithementioning

confidence: 72%

“…17 Further, we found that intraocular injections of glucagon peptide inhibits the proliferation of CMZ progenitors, and inhibition of the glucagon receptor increases the proliferation of CMZ progenitors. 17 The cells that produce the terminals that ramify in the CMZ were revealed to be unique types of cells that are distinct from the GACs. Within vertical sections of the retina, we occasionally observed unusual, glucagon-immunoreactive unipolar neurons with large somata in the INL, neurites in the distal inner plexiform layer (IPL), and axon-like structures that project toward the retinal periphery.…”

Section: Stem Cells Within the Retinal Margin And Nonpigmented Epithementioning

confidence: 72%

“…Within vertical sections of the retina, we occasionally observed unusual, glucagon-immunoreactive unipolar neurons with large somata in the INL, neurites in the distal inner plexiform layer (IPL), and axon-like structures that project toward the retinal periphery. 17,52 The axons of the large glucagonergic cells project to and ramify within the CMZ. 17 Cells similar to the large glucagon-expressing neurons were described more than two decades ago in a study that investigated the expression of substance P in ganglion cells; the unusual cells were described as having a morphology that is reminiscent of a bullwhip.…”

Section: Stem Cells Within the Retinal Margin And Nonpigmented Epithementioning

confidence: 99%

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Müller Glia, Vision-Guided Ocular Growth, Retinal Stem Cells, and a Little Serendipity

Fischer

2011

Invest. Ophthalmol. Vis. Sci.

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Hypothesis-driven science is expected to result in a continuum of studies and findings along a discrete path. By comparison, serendipity can lead to new directions that branch into different paths. Herein, I describe a diverse series of findings that were motivated by hypotheses, but driven by serendipity. I summarize how investigations into vision-guided ocular growth in the chick eye led to the identification of glucagonergic amacrine cells as key regulators of ocular elongation. Studies designed to assess the impact of the ablation of different types of neurons on vision-guided ocular growth led to the finding of numerous proliferating cells within damaged retinas. These proliferating cells were Müller glia-derived retinal progenitors with a capacity to produce new neurons. Studies designed to investigate Müller glia-derived progenitors led to the identification of a domain of neural stem cells that form a circumferential marginal zone (CMZ) that lines the periphery of the retina. Accelerated ocular growth, caused by visual deprivation, stimulated the proliferation of CMZ progenitors. We formulated a hypothesis that growth-regulating glucagonergic cells may regulate both overall eye size (scleral growth) and the growth of the retina (proliferation of CMZ cells). Subsequent studies identified unusual types of glucagonergic neurons with terminals that ramify within the CMZ; these cells use visual cues to control equatorial ocular growth and the proliferation of CMZ cells. Finally, while studying the signaling pathways that stimulate CMZ and Müller glia-derived progenitors, serendipity led to the discovery of a novel type of glial cell that is scattered across the inner retinal layers. (Invest Ophthalmol Vis Sci. 2011;52:7705-7710)

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Characterization of glucagon‐expressing neurons in the chicken retina

Fischer

Skorupa

Schonberg

et al. 2006

J of Comparative Neurology

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We recently identified large glucagon-expressing neurons that densely ramify neurites in the peripheral edge of the retina and regulate the proliferation of progenitors in the circumferential marginal zone (CMZ) of the postnatal chicken eye (Fischer et al. [2005] J Neurosci 25:10157-10166). However, nothing is known about the transmitters and proteins that are expressed by the glucagon-expressing neurons in the avian retina. We used antibodies to cell-distinguishing markers to better characterize the different types of glucagon-expressing neurons. We found that the large glucagon-expressing neurons were immunoreactive for substance P, neurofilament, Pax6, AP2alpha, HuD, calretinin, trkB, and trkC. Colocalization of glucagon and substance P in the large glucagon-expressing neurons indicates that these cells are the "bullwhip cells" that have been briefly described by Ehrlich et al. ([1987] J Comp Neurol 266:220-233). Similar to the bullwhip cells, the conventional glucagon-expressing amacrine cells were immunoreactive for calretinin, HuD, Pax6, and AP2alpha. Unlike bullwhip cells, the conventional glucagon-expressing amacrine cells were immunoreactive for GABA. While glucagon-immunoreactive amacrine cells were negative for substance P in central regions of the retina, a subset of this type of amacrine cell was immunoreactive for substance P in far peripheral regions of the retina. An additional type of glucagon/substance P-expressing neuron, resembling the bullwhip cells, was found in far peripheral and dorsal regions of the retina. Based on morphology, distribution within the retina, and histological markers, we conclude that there may be four different types of glucagon-expressing neurons in the avian retina.

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Glucagon-Expressing Neurons within the Retina Regulate the Proliferation of Neural Progenitors in the Circumferential Marginal Zone of the Avian Eye

Cited by 42 publications

References 41 publications

Patterning of the circumferential marginal zone of progenitors in the chicken retina

Patterning of the circumferential marginal zone of progenitors in the chicken retina

Müller Glia, Vision-Guided Ocular Growth, Retinal Stem Cells, and a Little Serendipity

Characterization of glucagon‐expressing neurons in the chicken retina

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