Retinal stem cells modulate proliferative parameters to coordinate post-embryonic morphogenesis in the eye of fish

Abstract

Combining clonal analysis with a computational agent based model, we investigate how tissue-specific stem cells for neural retina (NR) and retinal pigmented epithelium (RPE) of the teleost medaka (Oryzias latipes) coordinate their growth rates. NR cell division timing is less variable, consistent with an upstream role as growth inducer. RPE cells divide with greater variability, consistent with a downstream role responding to inductive signals. Strikingly, the arrangement of the retinal ciliary marginal zone niche results in a spatially biased random lineage loss, where stem- and progenitor cell domains emerge spontaneously. Further, our data indicate that NR cells orient division axes to regulate organ shape and retinal topology. We highlight an unappreciated mechanism for growth coordination, where one tissue integrates cues to synchronize growth of nearby tissues. This strategy may enable evolution to modulate cell proliferation parameters in one tissue to adapt whole-organ morphogenesis in a complex vertebrate organ.

dnmt1function is required to maintain retinal stem cells within the ciliary marginal zone of the zebrafish eye

“…RSCs within the teleost CMZ remain proliferative throughout the lifespan of the animal 3,55,56 and Dnmt1 is known to be required for cell cycle progression within stem cells of various tissue types 24,25,57 . Based on the significant loss of RSCs in dnmt1 -/larvae between 3-5dpf ( Figure 1) and the inability of dnmt1 -/-RSCs to maintain expression of cell cycle genes ( Figure 4), we hypothesized that dnmt1 -/-RSCs would be defective in their proliferative capacity.…”

Mouse Retinal Organoid Growth and Maintenance in Longer-Term Culture

“…Retinal ganglion cells are early-developing neurons in vertebrate retinas that express SHH, which promotes retinal progenitor proliferation and differentiation toward neuronal cell types ( Esteve and Bovolenta, 2006 ). Further, retinas in some animals grow by the addition of new neurons from a growth zone at the retinal margin ( Moshiri et al, 2004 ; Tsingos et al, 2019 ). Although this region is not involved in mouse and human development, it is part of their retinas ( Bhatia et al, 2009 ): progenitor expansion can be experimentally stimulated and involves SHH signaling ( Moshiri and Reh, 2004 ; Moshiri et al, 2004 , 2005 ; Bhatia et al, 2009 ; Christ et al, 2015 ).…”

Retinal Stem Cell ‘Retirement Plans’: Growth, Regulation and Species Adaptations in the Retinal Ciliary Marginal Zone

“…Although the different types of CMZ cells can be generally distinguished by different sets of molecular markers, lineage tracing of individual CMZ cells over time has confirmed the lineage relationship between them in vivo. Early transplantation studies [ 46 , 47 ] and, more recently, genetic-based lineage mapping [ 26 , 41 , 42 , 48 ] have shown that according to its spatial organization, the CMZ is indeed composed of both RSCs and RPCs. Continuously labelled clones tracked over time in the growing eye of teleost fish form characteristic labelled ‘stripes’ of displaced cells demarcating their origin and destination along the clone [ 41 , 46 , 48 ].…”

“…Early transplantation studies [ 46 , 47 ] and, more recently, genetic-based lineage mapping [ 26 , 41 , 42 , 48 ] have shown that according to its spatial organization, the CMZ is indeed composed of both RSCs and RPCs. Continuously labelled clones tracked over time in the growing eye of teleost fish form characteristic labelled ‘stripes’ of displaced cells demarcating their origin and destination along the clone [ 41 , 46 , 48 ]. Two different types of stripes/patches are commonly observed, including those that continuously label from the CMZ all the way into the central retina, termed arched continuous stripes (ArCoSs) [ 41 , 46 , 48 ], and those that label smaller stripe in the central retina that have become disconnected from the CMZ, termed ‘terminated patches’ [ 48 ] ( Figure 2 B).…”