Abstract
The vertebrate retina develops from a specified group of precursor cells that adopt distinct identities and generate lineages of either the neural retina, retinal pigmented epithelium, or ciliary body. In some species, including teleost fish and amphibians, proliferative cells with stem-cell-like properties capable of continuously supplying new retinal cells post-embryonically have been characterized and extensively studied. This region, termed the ciliary or circumferential marginal zone (CMZ), possibly represents a conserved retinal stem cell niche. In this review, we highlight the research characterizing similar CMZ-like regions, or stem-like cells located at the peripheral margin, across multiple different species. We discuss the proliferative parameters, multipotency and growth mechanisms of these cells to understand how they behave in vivo and how different molecular factors and signalling networks converge at the CMZ niche to regulate their activity. The evidence suggests that the mature retina may have a conserved propensity for homeostatic growth and plasticity and that dysfunction in the regulation of CMZ activity may partially account for dystrophic eye growth diseases such as myopia and hyperopia. A better understanding of the properties of CMZ cells will enable important insight into how an endogenous generative tissue compartment can adapt to altered retinal physiology and potentially even restore vision loss caused by retinal degenerative conditions.
Highlights
The identity of cell types and regulatory mechanisms required to build retinal tissue in the embryo are well known, but are similar mechanisms capable of maintaining retinal tissue later in life? How does this knowledge of early retinal development inform our understanding of the potential for ongoing growth in the mature retina? Early in development, the retina is formed from specified tissue of the neuroectoderm that undergoes morphogenetic changes to form the optic vesicle
The optic vesicle invaginates to form a two-layered tissue of neuroepithelial precursor cells referred to as the optic cup, where cells found in the inner layer give rise to the neural retina (NR), and cells in the surrounding tissue form the retinal pigmented epithelium (RPE)
The above research over the years has greatly improved our understanding of what controls proliferative dynamics in species with an active circumferential marginal zone (CMZ), mainly from teleost fish and amphibians, but the translation of the research found in zebrafish/amphibian models to other animal models, including mice and vice versa is lacking
Summary
The identity of cell types and regulatory mechanisms required to build retinal tissue in the embryo are well known, but are similar mechanisms capable of maintaining retinal tissue later in life? How does this knowledge of early retinal development inform our understanding of the potential for ongoing growth in the mature retina? Early in development, the retina is formed from specified tissue of the neuroectoderm that undergoes morphogenetic changes to form the optic vesicle. The neuroepithelial precursors specified to become the NR exhibit stem cell properties of self-renewal and multipotentiality, generating progeny that eventually differentiate to give rise to all seven retinal cell types organized into a tri-laminated structure. Other species, including teleost fish and amphibians, exhibit continuous growth in the retina over their entire lifetime [6,7] Corresponding to this growth, these species have a clearly identifiable source of actively proliferating neuroepithelial cells at the periphery of the NR, in a region termed the ciliary or circumferential marginal zone (CMZ). Other cell types of the eye, including the RPE, CE and Müller glia, have been found to exhibit stemcell-like characteristics in some organisms [6,8,9,10], but the peripheral NR shows the most consistent evidence of a stem cell niche, considering its spatial restriction and continuous growth activity in many vertebrates. Gthreeseen fcehaetuckrmesaarrkes ninodtipcaretesethnat,tadnadta‘?s’uipnpdoicrtastethsethpartesthenecdeaotfatihseisnesfuefafticuireenst, mtoagmenaktae‘Xa ’cionndcilcuastieosnt.hAatbdbarteavsiautgiognest:sCthMeZse=fecailtiuarreys maraerngiontaplrzeosnene,t,RaCnJd=‘?re’ tiinndoiccialitaersythjuantctthieond,aCtaMis=incisluiafrfiycimenatrgtoinm, CakBe=acciloianrcylubsoiodny.aAnbdbCreEv=iactiloinarsy: CepMitZhe=licuimlia.rAy qmuaersgtinoanl mzoanrke,iRs CuJse=drwetihneoncinlioatreynjuoungcthioenv,iCdeMnc=e ctiolidaraytemhaarsgbine,eCn Bfo=uncidliatorycobnocdlyudanedthCeEpr=esceilniacreyoefpaitChMeliZu-mli.kAe rqeugieosnti.on mark is used when not enough evidence to date has been found to conclude the presence of a CMZ-like region
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