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Barreiro-Iglesias, A. Proliferative Activity in Zebrafish Retina. Encyclopedia. Available online: (accessed on 01 December 2023).
Barreiro-Iglesias A. Proliferative Activity in Zebrafish Retina. Encyclopedia. Available at: Accessed December 01, 2023.
Barreiro-Iglesias, Antón. "Proliferative Activity in Zebrafish Retina" Encyclopedia, (accessed December 01, 2023).
Barreiro-Iglesias, A.(2021, December 03). Proliferative Activity in Zebrafish Retina. In Encyclopedia.
Barreiro-Iglesias, Antón. "Proliferative Activity in Zebrafish Retina." Encyclopedia. Web. 03 December, 2021.
Proliferative Activity in Zebrafish Retina

Researchers performed a systematic and comparative study of the constitutive proliferative activity of the retina from early developing (2 days post-fertilisation) to aged (up to 3–4 years post-fertilisation) zebrafish. 

Zebrafish Retina neurogenic proliferative

1. Introduction

Neurogenesis is the process by which neural progenitor cells give rise to mature neurons and glial cells. Early in development, the central nervous system (CNS) is formed from a highly active neurogenic neuroepithelium. As development progresses, proliferative and neurogenic activities are gradually lost in most CNS regions, and, in postnatal life, neurogenic activity is restricted to specific regions called neurogenic niches [1][2]. Moreover, the presence of postnatal neurogenic activity in the CNS was also progressively lost during vertebrate evolution (reviewed in [3][4][5][6][7][8]). Accordingly, different vertebrate species show different postnatal/adult proliferative and neurogenic rates and different numbers of neurogenic niches in the CNS, which are more abundant in teleost fishes (reviewed in [3][4][5][6][7][8][9]). Some postnatal constitutive and/or inducible (e.g., during regeneration) neurogenic niches are found in the retina of vertebrates. These include the ciliary marginal zone (CMZ), which is a circumferential ring of cells located in the peripheral retina [10][11][12][13][14][15]; the Müller glial cells of the inner nuclear layer (INL) of the central retina [12][16][17][18][19]; the retinal pigment epithelium (RPE; [20][21][22]), a pseudostratified region at the junction between the retina and the ciliary body [23]; and the pigmented and non-pigmented epithelium of the ciliary body [24][25][26][27][28]. The proliferative and neurogenic capacities of each of these retinal neurogenic niches varies in different vertebrate species (reviewed in [19][29][30][31]). In fishes, all retinal cell types, except rod photoreceptors, are generated within the CMZ and incorporated to the most peripheral region of the central retina (so that older cells remain in the central retina and new cells become located successively in more peripheral positions). Instead, rod photoreceptors are continuously generated from Müller glia in the central retina.
Based on studies in teleost species, it is largely assumed that the retina of fishes, in contrast to mammals, has continuous proliferative activity throughout life and that this (together with tissue stretching) is partially responsible for continuous eye growth, even during adulthood. This idea emerges in relevant articles on this topic during the last decades: “Fish retinas differ fundamentally from those of other vertebrates because they continue to grow throughout the life of the animal, both by adding new neurons and by stretching existing retinal tissue” [32]; “In fish and amphibia, retinal stem cells located in the periphery of the retina, the ciliary marginal zone (CMZ), produce new neurons in the retina throughout life” [33]; “The retina of many fish and amphibians grows throughout life, roughly matching the overall growth of the animal. The new retinal cells are continually added at the anterior margin of the retina, in a circumferential zone of cells” [34]; “The retinas of lower vertebrates grow throughout life from retinal stem cells (RSCs) and retinal progenitor cells (RPCs) at the rim of the retina” [35]; “In the retina of teleost fish, cell addition continues throughout life involving proliferation and axonal growth” [36], to name a few. However, studies in the sea lamprey, Petromyzon marinus, and the catshark, Scyliorhinus canicula, revealed the loss of proliferative activity in the retina of adult individuals of these ancient vertebrate groups [37][38]. This raised the possibility that continuous proliferative activity throughout life in the retina was a derived characteristic of modern teleost fishes and not the ancestral character common to all fish groups [38].

2. Current Studies

It is largely assumed that the retina of fishes shows continuous and active proliferation and neurogenesis throughout life. This assumption is based on previous work in teleost models in which the presence of proliferating cells was only studied in juveniles or young adults, in animals in which the precise age was not defined or known by the authors of the study, or without performing quantitative comparisons between all life stages or ages. This feature of throughout-life neurogenesis does not apply to lampreys or cartilaginous fishes, in which proliferative activity is virtually absent in adult animals [37][38]. Moreover, some of the previous studies on teleost fishes provided qualitative descriptions that also suggested a loss of proliferating cells with age. For example, Johns and Fernald [39] reported that, when studying African cichlid and goldfish juveniles and adults, the dividing cells in the ONL were easier to demonstrate in younger fish. In zebrafish, Marcus et al. [40] also indicated that the number of BrdU labelled cells was greater in the CMZ and central retina of embryos than in young adults (6–8 mpf). A recent study by Van Houcke et al. [41] showed a decline in the cell proliferation (PCNA+ cells) in the zebrafish CMZ from 6 to 48 mpf. However, the proliferation within the central retina of zebrafish was not quantified over time. Besides, the assessment of progenitor cell proliferation relied only on PCNA expression, which, despite its use, can lead to the overestimation of proliferation in aged animals (see the Introduction).
Here, researchers obtained quantitative data comparing the cell cycle progression (PCNA+ cells/section) and mitotic activity (pH3+ cells/section) in both the CMZ and the central zebrafish retina at different ages and covering all major life stages. Results show that there is a drastic decline in proliferative activity from 2 to 7 dpf, a continuous reduction in the number of proliferating cells in sexually maturing and old animals, and that cells undergoing mitosis are virtually absent in old animals. This is in good agreement with previous reports of a drastic decrease in cell proliferation in early larvae (between the 3 dpf and 4 dpf; [40]) and with reports of a significant proliferation decrease in early adulthood (6–12 mpf), with very reduced proliferation rates at the mid (18–24 mpf) and late (36–38 mpf) adult stages [41]. As expected, the number of PCNA+ cells reported in the CMZ by Van Houcke et al. [41] was higher than that of pH3+ cells in this region at similar life stages (present results) since the latter are only a fraction of the number of cells progressing through the cell cycle. Results in zebrafish reveal a similar pattern to that reported in lampreys and sharks showing a loss of the proliferating and mitotic cells in the adult retina [37][38]. However, it seems that retinal proliferative activity is maintained at a higher rate in adult zebrafish than in adult lampreys (no PCNA+ cells; [37]) or sharks (very few PCNA+ cells and almost no pH3+ cells; [38]).
Unlike previous reports on the proliferation in the zebrafish retina, the new systematic analysis allowed unveiling the occurrence of a secondary wave of proliferation during sexual maturation (i.e., from 1.5 to 3 mpf) affecting both the CMZ and the central retina. Only a study by Bernardos et al. [17] provided a qualitative description indicating that BrdU+ cells in the ONL were observed in higher numbers in 1 to 2 mpf animals than in 7 dpf animals. This increase in the cell proliferation at 1.5 mpf (present results) did not reach the levels of the early developing (2 dpf) period, but it was significantly higher than in the 7 dpf specimens. This secondary wave of proliferation could be related to an earlier peak of cell death that occurs in the retina (especially in the ONL) of 7 dpf zebrafish [42]. This increase in cell proliferation could allow for the replacement of the cells lost during this critical period in which fish transition from acquiring nutrition from their yolk to active feeding. This secondary wave of proliferation could also be related to retinal adaptations that might be needed for sexual behaviours, especially since the integration of multi-sensory information between olfaction and vision has been implicated in mating-like behaviours in zebrafish [43]. However, current data have only implicated dopaminergic interplexiform and retinal ganglion cells in this olfacto–visual centrifugal pathway [43], which would not explain why proliferation and neurogenesis are needed in the ONL (see below). Future studies should decipher whether this secondary wave of proliferation is only needed to replace lost retinal cells or if it is related to retinal adaptations needed for sexual (or adult) behaviours in zebrafish.
By looking at the distribution of the proliferating/mitotic cells in the cell layers of the central retina at different ages, researchers observed that, in early developing 4 dpf specimens, the numbers of pH3+ and PCNA+ cells were higher in the INL, whereas, in older animals, they were more abundant in the ONL. Previous studies have shown that the progenitor cells of the central retina (Müller glia) in juvenile/adult goldfish [39][44][45] and in juvenile zebrafish [17][46][47][48] generate new rods, which indicates that the higher cell proliferation and mitotic activity researchers observed in the ONL of juvenile and adult zebrafish is related to rod generation. As far as researchers are aware, the generation of other retinal cell types from the INL and ONL progenitors of the un-injured juvenile/adult teleost retina has not been reported, although injury-induced proliferating Müller glial cells can regenerate all the retinal cell types, including cones [17][46][47][48], which has led to the suggestion that the neuronal progenitors produced by Müller glia are multipotent and can revert to an earlier lineage under the influence of certain microenvironmental signals [17][46][47][49]. The zebrafish retina presents five main types of photoreceptors (four cones and one rod), and the five types of photoreceptors are generated during early development [50][51]. Perhaps one or more of these photoreceptor types are specifically needed for mating/courtship/adult behaviours and could be generated in extra numbers during sexual maturation, which could explain the secondary wave of cell proliferation researchers detected in zebrafish juveniles. Since, during courtship and spawning, female zebrafish discriminate between the sexes using visual cues in which the male yellow colouration is critical [51], it is tempting to hypothesise that specific cones might be needed at this life stage. However, microenviromental signals other than retinal injury driving cone generation from progenitors in the central retina have not been experimentally assessed. Future work should attempt to study whether cones could also be generated from these dividing progenitor cells of the central retina, especially during the previously undetected secondary wave of proliferation at the time of sexual maturation.


  1. Doetsch, F. A niche for adult neural stem cells. Curr. Opin. Genet. Dev. 2003, 13, 543–550.
  2. Álvarez-Buylla, A.; Lim, D.A. For the long run: Maintaining germinal niches in the adult brain. Neuron 2004, 41, 683–686.
  3. Ferretti, P. Is there a relationship between adult neurogenesis and neuron generation following injury across evolution? Eur. J. Neurosci. 2011, 34, 951–962.
  4. Zupanc, G.K.; Sîrbulescu, R.F. Adult neurogenesis and neuronal regeneration in the central nervous system of teleost fish. Eur. J. Neurosci. 2011, 34, 917–929.
  5. Grandel, H.; Brand, M. Comparative aspects of adult neural stem cell activity in vertebrates. Dev Genes Evol. 2013, 223, 131–147.
  6. Than-Trong, E.; Bally-Cuif, L. Radial glia and neural progenitors in the adult zebrafish central nervous system. Glia 2015, 63, 1406–1428.
  7. Alunni, A.; Bally-Cuif, L. A comparative view of regenerative neurogenesis in vertebrates. Development 2016, 143, 741–753.
  8. Zupanc, G.K.H. Adult neurogenesis in the central nervous system of teleost fish: From stem cells to function and evolution. J. Exp. Biol. 2021, 224, jeb226357.
  9. Miles, A.; Tropepe, V. Retinal stem cell ‘retirement plans’: Growth, regulation and species adaptations in the retinal ciliary marginal zone. Int. J. Mol. Sci. 2021, 22, 6528.
  10. Harris, W.A.; Perron, M. Molecular recapitulation: The growth of the vertebrate retina. Int. J. Dev. Biol. 1998, 42, 299–304.
  11. Fischer, A.J. Neural regeneration in the chick retina. Prog. Retin. Eye Res. 2005, 24, 161–182.
  12. Raymond, P.A.; Barthel, L.K.; Bernardos, R.I.; Perkowski, J.J. Molecular characterization of retinal stem cells and their niches in adult zebrafish. BMC Develop. Biol. 2006, 6, 36.
  13. Fischer, A.J.; Bosse, J.L.; El-Hodiri, M. The ciliary marginal zone (CMZ) in development and regeneration of the vertebrate eye. Exp. Eye Res. 2013, 116, 199–204.
  14. Marcucci, F.; Murcia-Belmonte, V.; Wang, Q.; Coca, Y.; Ferreiro-Galve, S.; Kuwajima, T.; Khalid, S.; Ross, M.E.; Mason, C.; Herrera, E. The ciliary margin zone of the mammalian retina generates retinal ganglion cells. Cell Rep. 2016, 17, 3153–3164.
  15. Bélanger, M.C.; Robert, B.; Cayouette, M. Msx1-positive progenitors in the retinal ciliary margin give rise to both neural and non-neural progenies in mammals. Dev. Cell. 2017, 40, 137–150.
  16. Fausett, B.V.; Goldman, D. A role for α1 tubulin-expressing Müller glia in regeneration of the injured zebrafish retina. J. Neurosci. 2006, 26, 6303–6313.
  17. Bernardos, R.L.; Barthel, L.K.; Meyers, J.R.; Raymond, P.A. Late-stage neuronal progenitors in the retina are radial Müller glia that function as retinal stem cells. J. Neurosci. 2007, 27, 7028–7040.
  18. Nagashima, M.; Barthel, L.K.; Raymond, P.A. A self-renewing division of zebrafish Müller glial cells generates neuronal progenitors that require N-cadherin to regenerate retinal neurons. Development 2013, 140, 4510–4521.
  19. Wilken, M.S.; Reh, T.A. Retinal regeneration in birds and mice. Curr. Opin. Genet. Dev. 2016, 40, 57–64.
  20. Okada, T.S. Cellular metaplasia or transdifferentiation as a model for retinal cell differentiation. Curr. Top. Dev. Biol. 1980, 16, 349–380.
  21. Engelhardt, M.; Bogdahn, U.; Aigner, L. Adult retinal pigment epithelium cells express neural progenitor properties and the neuronal precursor protein doublecortin. Brain Res. 2005, 1040, 98–111.
  22. Ma, R.T.Y.; Li, X.; Wang, S.Z. Reprogramming RPE to differentiate towards retinal neurons with Sox2. Stem Cells 2009, 27, 1376–1387.
  23. Eymann, J.; Salomies, L.; Macrì, S.; Di-Poï, N. Variations in the proliferative activity of the peripheral retina correlate with postnatal ocular growth in squamate reptiles. J. Comp. Neurol. 2019, 527, 2356–2370.
  24. Tropepe, V.; Coles, B.L.; Chiasson, B.J.; Horsford, D.J.; Elia, A.J.; McInnes, R.R.; van der Kooy, D. Retinal stem cells in the adult mammalian eye. Science 2000, 287, 2032–2036.
  25. Fischer, A.J.; Reh, T.A. Transdifferentiation of pigmented epithelial cells: A source of retinal stem cells? Dev. Neurosci. 2001, 23, 268–276.
  26. Fischer, A.J.; Reh, T.A. Growth factors induce neurogenesis in the ciliary body. Dev. Biol. 2003, 259, 225–240.
  27. Das, A.V.; James, J.; Rahnenführer, J.; Thoreson, W.B.; Bhattacharya, S.; Zhao, X.; Ahmad, I. Retinal properties and po-tential of the adult mammalian ciliary epithelium stem cells. Vision Res. 2005, 45, 1653–1666.
  28. Das, A.V.; Zhao, X.; James, J.; Kim, M.; Cowan, K.H.; Ahmad, I. Neural stem cells in the adult ciliary epithelium express GFAP and are regulated by Wnt signaling. Biochem. Biophys. Res. Commun. 2006, 339, 708–716.
  29. Reh, T.A.; Fischer, A.J. Stem cells in the vertebrate retina. Brain Behav. Evol. 2001, 58, 296–305.
  30. Amato, M.A.; Arnault, E.; Perron, M. Retinal stem cells in vertebrates: Parallels and divergences. Int. J. Dev. Biol. 2004, 48, 993–1001.
  31. Moshiri, A.; Close, J.; Reh, T.A. Retinal stem cells and regeneration. Int. J. Dev. Biol. 2004, 48, 1003–1014.
  32. Fernald, R.D. Teleost vision: Seeing while growing. J. Exp. Zool. 1991, 5, 167–180.
  33. Perron, M.; Harris, W.A. Retinal stem cells in vertebrates. Bioessays 2000, 22, 685–688.
  34. Kubota, R.; Hokoc, J.N.; Moshiri, A.; McGuire, C.; Reh, T.A. A comparative study of neurogenesis in the retinal ciliary marginal zone of homeothermic vertebrates. Dev. Brain Res. 2002, 134, 31–41.
  35. Wan, Y.; Almeida, A.D.; Rulands, S.; Chalour, N.; Muresan, L.; Wu, Y.; Simons, B.D.; He, J.; Harris, W.A. The ciliary marginal zone of the zebrafish retina: Clonal and time-lapse analysis of a continuously growing tissue. Development 2016, 143, 1099–1107.
  36. García-Pradas, L.; Gleiser, C.; Wizenmann, A.; Wolburg, H.; Mack, A.F. Glial cells in the fish retinal nerve fiber layer form tight junctions, separating and surrounding axons. Front. Mol. Neurosci. 2018, 11, 367.
  37. Villar-Cheda, B.; Abalo, X.M.; Villar-Cerviño, V.; Barreiro-Iglesias, A.; Anadón, R.; Rodicio, M.C. Late proliferation and photoreceptor differentiation in the transforming lamprey retina. Brain Res. 2008, 1201, 60–67.
  38. Hernández-Núñez, I.; Robledo, D.; Mayeur, H.; Mazan, S.; Sánchez, L.; Adrio, F.; Barreiro-Iglesias, A.; Candal, E. Loss of active neurogenesis in the adult shark retina. Front. Cell Dev. Biol. 2021, 9, 628721.
  39. Johns, P.R.; Fernald, R.D. Genesis of rods in teleost fish retina. Nature 1981, 293, 141–142.
  40. Marcus, R.C.; Delaney, C.L.; Easter, S.S., Jr. Neurogenesis in the visual system of embryonic and adult zebrafish (Danio rerio). off. Vis. Neurosci. 1999, 16, 417–424.
  41. Van Houcke, J.; Geeraerts, E.; Vanhunsel, S.; Beckers, A.; Noterdaeme, L.; Christiaens, M.; Bollaerts, I.; De Groef, L.; Moons, L. Extensive growth is followed by neurodegenerative pathology in the continuously expanding adult zebrafish retina. Biogerontology 2019, 20, 109–125.
  42. Biehlmaier, O.; Neuhauss, S.C.; Kohler, K. Onset and time course of apoptosis in the developing zebrafish retina. Cell Tissue Res. 2001, 306, 199–207.
  43. Li, L.; Wojtowicz, J.L.; Malin, J.H.; Huang, T.; Lee, E.B.; Chen, Z. GnRH-mediated olfactory and visual inputs promote mating-like behaviors in male zebrafish. PLoS ONE 2017, 12, e0174143.
  44. Johns, P.R. Formation of photoreceptors in larval and adult goldfish. J. Neurosci. 1982, 2, 178–198.
  45. Otteson, D.C.; D’Costa, A.R.; Hitchcock, P.F. Putative stem cells and the lineage of rod photoreceptors in the mature retina of the goldfish. Dev. Biol. 2001, 232, 62–76.
  46. Morris, A.C.; Scholz, T.L.; Brockerhoff, S.E.; Fadool, J.M. Genetic dissection reveals two separate pathways for rod and cone regeneration in the teleost retina. Dev. Neurobiol. 2008, 68, 605–619.
  47. Morris, A.C.; Scholz, T.; Fadool, J.M. Rod progenitor cells in the mature zebrafish retina. Adv. Exp. Med. Biol. 2008, 613, 361–368.
  48. Lenkowski, J.R.; Raymond, P.A. Müller glia: Stem cells for generation and regeneration of retinal neurons in teleost fish. Prog. Retin. Eye Res. 2014, 40, 94–123.
  49. Stenkamp, D.L. The rod photoreceptor lineage of teleost fish. Prog. Retin. Eye Res. 2011, 30, 395–404.
  50. Crespo, C.; Knust, E. Characterisation of maturation of photoreceptor cell subtypes during zebrafish retinal development. Biol. Open. 2018, 7, bio036632.
  51. Hutter, S.; Hettyey, A.; Penn, D.J.; Zala, S.M. Ephemeral sexual dichromatism in zebrafish (Danio rerio). Ethology 2012, 118, 1208–1218.
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