Cone photoreceptor types in zebrafish are generated by symmetric terminal divisions of dedicated precursors

Abstract

Proper functioning of sensory systems requires the generation of appropriate numbers and proportions of neuronal subtypes that encode distinct information. Perception of color relies on signals from multiple cone photoreceptor types. In cone-dominated retinas, each cone expresses a single opsin type with peak sensitivity to UV, long (L) (red), medium (M) (green), or short (S) (blue) wavelengths. The modes of cell division generating distinct cone types are unknown. We report here a mechanism whereby zebrafish cone photoreceptors of the same type are produced by symmetric division of dedicated precursors. Transgenic fish in which the thyroid hormone receptor β2 (trβ2) promoter drives fluorescent protein expression before L-cone precursors themselves are produced permitted tracking of their division in vivo. Every L cone in a local region resulted from the terminal division of an L-cone precursor, suggesting that such divisions contribute significantly to L-cone production. Analysis of the fate of isolated pairs of cones and time-lapse observations suggest that other cone types can also arise by symmetric terminal divisions. Such divisions of dedicated precursors may help to rapidly attain the final numbers and proportions of cone types (L > M, UV > S) in zebrafish larvae. Loss-and gain-of-function experiments show that L-opsin expression requires trβ2 activity before cone differentiation. Ectopic expression of trβ2 after cone differentiation produces cones with mixed opsins. Temporal differences in the onset of trβ2 expression could explain why some species have mixed, and others have pure, cone types.vertebrate cone photoreceptors | cone genesis | zebrafish retina | in vivo time-lapse imaging T he proper functioning of neuronal circuits requires the generation and wiring of a diversity of neuronal cell types. A single neuronal cell class often comprises many subtypes that share similar properties, such as neurotransmitter phenotype, but differ in their precise molecular expression profile, morphology, and physiology (1, 2). How neuronal subtypes that share connectivity with the same populations of postsynaptic cells are produced is not well understood, particularly for vertebrate circuits in vivo. Specifically, are distinct presynaptic partner types of a given postsynaptic cell generated together or produced from separate divisions? When during cell genesis do the presynaptic cell types adopt their respective identities?Cell lineage analyses have demonstrated that many neurogenic divisions are asymmetric, sometimes producing distinct neuronal classes or a neuron together with a nonneuronal cell type (3, 4). Examples of progenitors that give rise to a single neuronal class have also been reported (5-13). A single progenitor, however, can also produce two distinct neuronal subtypes (14-17). In some instances, neurons of the same functional subtype may also share a common progenitor (18), but their generation may involve both symmetric and asymmetric divisions (13,19,20). Recent retroviral studies in chick retina r...

Dynamical pattern selection of growing cellular mosaic in fish retina

“…The rearrangement of those new cone cells after cellular differentiation is considered to play a crucial role in mosaic pattern formation. This is supported by a cell-trace experiment in which most of the cells are found not to change their subtypes after the * Electronic address: noriaki@riken.jp † Electronic address: thatsuda@riken.jp ‡ Electronic address: mochi@riken.jp § Electronic address: mtach@riken.jp first determination [5]. Theoretically, cell rearrangement models for cone mosaics have been formulated on a two-dimensional square lattice: It was found that different patterns (such as the zebrafish pattern with c2mm symmetry and the medaka pattern with p4mg symmetry) can be generated successfully by stochastic cell movements biased by appropriate cell-cell adhesion force [6][7][8].…”

“…The true coefficients are known to be rational numbers, so that the above coefficients must be exact although obtained numerically. We find that |λ 5,6,7,8 | are degenerated up to O(g 3 ), and the O(g 7/2 ) contributions start to break the degeneracy. Also, λ 6,7 acquire nonzero real parts from O(g 7/2 ).…”

Photoreceptor cell fate specification in vertebrates

“…This is because in lineagetracing studies two-cell clones derived from Olig2 + , Neurog2 + and Ascl1 + progenitors sometimes contain two photoreceptors and sometimes a photoreceptor and a non-photoreceptor type (Brzezinski et al, 2011;Hafler et al, 2012). Live imaging experiments in zebrafish show that terminal divisions can generate similar diversity, although there are also lineage-restricted cone and rod progenitors (Godinho et al, 2007;He et al, 2012;Suzuki et al, 2013). These results imply that the specification events that define rod and cone fates are not strictly linked to the status of the cell cycle.…”

“…However, this is not always the case; it has been known for many years that teleost fish (e.g. zebrafish and goldfish) possess a progenitor that is restricted to producing only rod photoreceptors, although this has been considered an adaptation to maintain light sensitivity and rod density as the retina grows in postembryonic stages (Raymond and Rivlin, 1987), and more recent studies have provided evidence for horizontal-and cone-restricted progenitors in fish (Godinho et al, 2007;He et al, 2012;Suzuki et al, 2013). Together, these studies suggest that many of the specification events leading to the generation of photoreceptors, and even their specific subtype, can occur in either proliferative progenitor or postmitotic precursor (see Glossary, Box 1) cells.…”

Thyroid disruption in zebrafish (Danio rerio) larvae: Different molecular response patterns lead to impaired eye development and visual functions

“…Knock-down of specific thyroid-regulating genes as well as treatment with different thyroid disruptors resulted in reduced eye size, malformations of eyes and head, and disruption of retinal pigment cell layers of zebrafish larvae (Heijlen et al, 2014;Reider and Connaughton, 2014). It has been reported that cone photoreceptor development seems to be under direct regulation of thyroid hormones (Raine and Hawryshyn, 2009;Suzuki et al, 2013), and it has been described, that thyroid receptors are expressed in the outer nuclear layer of the retina, which contains the developing photoreceptors (Bertrand et al, 2007). The exact pathways still need further investigation, even though a recent study could show that different genes involved in phototransduction are changed in their expression after knockdown of deiodinase enzymes in zebrafish, which regulate intracellular thyroid hormone levels (Bagci et al, 2015).…”