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WIREs Dev Biol
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Through veiled mirrors: Fish fins giving insight into size regulation

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Abstract Faithful establishment and maintenance of proportion is seen across biological systems and provides a glimpse at fundamental rules of scaling that underlie development and evolution. Dysregulation of proportion is observed in a range of human diseases and growth disorders, indicating that proper scaling is an essential component of normal anatomy and physiology. However, when viewed through an evolutionary lens, shifts in the regulation of relative proportion are one of the most striking sources of morphological diversity among organisms. To date, the mechanisms via which relative proportion is specified and maintained remain unclear. Through the application of powerful experimental, genetic and molecular approaches, the teleost fin has provided an effective model to investigate the regulation of scaling, size, and relative growth in vertebrate organisms. This article is categorized under: Establishment of Spatial and Temporal Patterns > Regulation of Size, Proportion, and Timing Adult Stem Cells, Tissue Renewal, and Regeneration > Regeneration Comparative Development and Evolution > Regulation of Organ Diversity
Perceptions of proportion. (a) Drawing reprinted with permission from Tobin (1975) illustrating search for mathematical underpinnings of “ideal” proportions by artists such as Polykleitos. (b) Like ancient cultures before him, Dürer used a grid system to reliably capture adult form. He then warped this grid to illustrate shifts in morphology (Dürer, 1528). (c) Inspired by Dürer, D'Arcy Thompson used grid transformations to model relative growth as means for evolutionary variation (Thompson, 1917)
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Keeping growth in check and means of size regulation. (a) miR‐133 controls the progress of fin regeneration through regulation of msp1 activity. Similarly, miR‐133 also was found to regulate both kcnk5b and cx43 in regenerating fins (Yin et al., 2008). These findings raise the hypothesis that size may be regulated by broad dampening of growth‐promoting signals, including bioelectric signaling circuits that regulate proportion. (b) A prediction of the relationship between kcnk5b/cx43 and miR‐133 in establishing allometric growth and maintaining stasis in organ size during development
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Experimental analysis of regeneration and evidence for disparity as a signal for size. Top, Blastema transplantations reveal lack of positional determination within blastemal cells. Transplantation of blastemas from different proximal–distal levels to a common proximal site leads to similar contribution and growth from transplants (After Shibata et al., 2018). Bottom, Regeneration in context of missing tissue. Fins that undergo amputation in the presence of Wnt or Fgf‐signaling inhibitors form wound epidermis but do not initiate regeneration, even if inhibition is subsequently removed after wound healing. If a proximal fin segment is also removed at the time of amputation (*), wound healing (but not regeneration) will still occur, causing a local disparity in tissue architecture. If a superficial injury is applied to the distal epidermis once healing is complete (black bar), regeneration is initiated locally and lost skeletal material reforms. Reprinted with permission from Owlarn et al. (2017)
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Position writ large. Expression profiling of fins reveal distinct PD (caudal fin) and AP (pectoral fin) specification of fin rays. Reprinted with permission from Rabinowitz et al. (2017) and Nachtrab, Kikuchi, Tornini, and Poss (2013)
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Anatomy of a fin. Left, Adult zebrafish outward morphology showing position and size of paired and medial fins. Placement and general size of fins are consistent among zebrafish and show little individual variability. Fin rays are comprised of smaller segmented skeletal units formed by intramembraneous ossification. These skeletal units can branch and have filaments extending along length of each ray, actinotrichia, that project outward from the distal‐most segments. Reprinted with permission from Daane et al., 2018. Right, Schematic of anatomical complexity of a fin ray cross‐section (Reprinted with permission from Perathoner, 2012)
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Bioelectric algebra as a means for coordinated development and scaling of zebrafish fins. (a) Modulation of kcnk5b signaling through conductance and secondary modulation of C‐terminus. Cln, calcineurin; Ga, small g‐coupled proteins; PLC, Phospholipase C. Reprinted with permission from Perathoner et al. (2014). (b) Additive function of potassium channel function to regulate resting membrane potential (Vmem). WNK, WNK kinases. Both kcc4a (green) and kcnk5b (light blue) modulate conductance in response to changes in pH, swelling, and other physiological conditions. Conductance can be modulated by internal growth signals, both small G‐coupled signaling factors stemming from IGF signaling and Ca++ fluxes. Resting membrane potential can also be affected by action of v‐ATPase and its regulation of mTOR activity and growth regulation (Takayama, Muto, & Kikuchi, 2018). Following, additive changes in Vmem may be a common readout for growth mediated by action of kcnk5b. (c, d) Changes in Vmem can cause changes in ion potential within and between cells. (c) Connexins electronically couple neighboring cells and allow for dissemination of small ions and molecules, thereby altering Vmem of juxtaposed cells. (d) If gap junctions are not present or impaired, such coupling will be limited causing more localized effect of growth and environmental signals (Hoptak‐Solga, Klein, DeRosa, White, & Iovine, 2007). (b–d) Reprinted with permission from Lanni et al. (2019)
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Genetic regulation and growth rate. (a) Regeneration profiles of zebrafish long‐ and short‐finned mutants recapitulate growth properties seen in development. (b) However, upon normalization to starting fin size, the regenerative response observed in the scaling mutants is comparable to that of wild‐type fish, with amputated fins completing regrowth in the same time frame irrespective of their target length. (c) Treatment of regenerating fins (gray lines) with the drug FK506 (colored as in a) leads to overgrowth of all genotypes similar to that seen in the alf/kcnk5b mutant. (d) Deletion of kcnk5b leads to loss of FK506‐mediated overgrowth. Reprinted with permission from Daane et al. (2018)
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Outward scaling phenotypes in the adult zebrafish. Left, Zebrafish mutants showing changes in fin size due to mutation. Right, Two classes of fin mutants dissociate fin size from segment patterning. One class of mutants affects genes that regulate growth rate (another longfin (alf), schleier (schl), and shortfin (sof)) but maintain normal scaling, whereas another class exhibits relatively normal rates of growth but a greater number of skeletal elements (longfin (lof)); in the latter case, the mechanism of scaling has been lost or bypassed. Note presence of extended length in barbules in long‐finned mutants shown—barbule overgrowth is seen in the class of mutants that show altered growth rate (alf, schl) but not in lof mutants suggesting different mechanisms regulating size between the mutants and between structures
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Fitting to size: Regeneration and growth rate modeling. (a) Schematic of an idealized fin regeneration experiment using the pectoral fin with an unamputated contralateral fin serving as a size control. Similar experiments performed on caudal fin lobes show comparable data. At time 0, one fin is amputated a set distance along the fin proximodistal axis. Regeneration leads to growth of the appendage until it reaches its starting size (t1); Reprinted with permission from Daane et al. (2018). (b) Schematic of results of classic experiments showing that more proximal cuts have a faster growth rate during regeneration than more distal cuts. The end result is that all fins generally finish regeneration in a comparable time frame. (c) Normalization of growth response relative to starting size of the fin shows that the rate of fin regeneration is scaled by the extent of the remaining fin fragment
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Comparative Development and Evolution > Regulation of Organ Diversity
Adult Stem Cells, Tissue Renewal, and Regeneration > Regeneration
Establishment of Spatial and Temporal Patterns > Regulation of Size, Proportion, and Timing