scholarly journals Skeletal geometry and niche transitions restore organ size and shape during zebrafish fin regeneration

2019 ◽  
Author(s):  
Scott Stewart ◽  
Gabriel A. Yette ◽  
Heather K. Le Bleu ◽  
Astra L. Henner ◽  
Joshua A. Braunstein ◽  
...  
Keyword(s):  
Mathematical Modeling ◽  
Positional Information ◽  
State Transitions ◽  
Injury Site ◽  
Fin Regeneration ◽  
Size And Shape ◽  
Fin Rays ◽  
Fish Fins ◽  
Original Size ◽  
Skeletal Geometry

ABSTRACTRegenerating fish fins return to their original size and shape regardless of the nature or extent of injury. Prevailing models for this longstanding mystery of appendage regeneration speculate fin cells maintain uncharacterized positional identities that instruct outgrowth after injury. Using zebrafish, we find differential Wnt production correlates with the extent of regeneration across the caudal fin. We identify Dachshund transcription factors as markers of distal blastema cells that produce Wnt and thereby promote a pro-progenitor and -proliferation environment. We show these Dach-expressing “niche cells” derive from mesenchyme populating cylindrical and progressively tapered fin rays. The niche pool, and consequently Wnt, steadily dissipates as regeneration proceeds; once exhausted, ray and fin growth stops. Supported by mathematical modeling, we show longfint2 zebrafish regenerate exceptionally long fins due to a perdurant niche, representing a “broken countdown timer”. We propose regenerated fin size is dictated by the amount of niche formed upon damage, which simply depends on the availability of intra-ray mesenchyme defined by skeletal girth at the injury site. Likewise, the fin reestablishes a tapered ray skeleton because progenitor osteoblast output reflects diminishing niche size. This “transpositional scaling” model contends mesenchyme-niche state transitions and positional information provided by self-restoring skeletal geometry rather than cell memories determine a regenerated fin’s size and shape.

Involvement of the sonic hedgehog, patched 1 and bmp2 genes in patterning of the zebrafish dermal fin rays

Development ◽  
1998 ◽  
Vol 125 (21) ◽  
pp. 4175-4184 ◽  
Author(s):  
L. Laforest ◽  
C.W. Brown ◽  
G. Poleo ◽  
J. Geraudie ◽  
M. Tada ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Sonic Hedgehog ◽  
Bone Matrix ◽  
Basal Layer ◽  
Pectoral Fin ◽  
Expression Domain ◽  
Fin Regeneration ◽  
Fin Rays ◽  
Dermal Bone ◽  
Fish Fins

The signaling molecule encoded by Sonic hedgehog (shh) participates in the patterning of several embryonic structures including limbs. During early fin development in zebrafish, a subset of cells in the posterior margin of pectoral fin buds express shh. We have shown that regulation of shh in pectoral fin buds is consistent with a role in mediating the activity of a structure analogous to the zone of polarizing activity (ZPA) (Akimenko and Ekker (1995) Dev. Biol. 170, 243–247). During growth of the bony rays of both paired and unpaired fins, and during fin regeneration, there does not seem to be a region equivalent to the ZPA and one would predict that shh would play a different role, if any, during these processes specific to fish fins. We have examined the expression of shh in the developing fins of 4-week old larvae and in regenerating fins of adults. A subset of cells in the basal layer of the epidermis in close proximity to the newly formed dermal bone structures of the fin rays, the lepidotrichia, express shh, and ptc1 which is thought to encode the receptor of the SHH signal. The expression domain of ptc1 is broader than that of shh and adjacent blastemal cells releasing the dermal bone matrix also express ptc1. Further observations indicate that the bmp2 gene, in addition to being expressed in the same cells of the basal layer of the epidermis as shh, is also expressed in a subset of the ptc1-expressing cells of the blastema. Amputations of caudal fins immediately after the first branching point of the lepidotrichia, and global administration of all-trans-retinoic acid, two procedures known to cause fusion of adjacent rays, result in a transient decrease in the expression of shh, ptc1 and bmp2. The effects of retinoic acid on shh expression occur within minutes after the onset of treatment suggesting direct regulation of shh by retinoic acid. These observations suggest a role for shh, ptc1 and bmp2 in patterning of the dermoskeleton of developing and regenerating teleost fins.

scholarly journals longfin causes cis-ectopic expression of the kcnh2a ether-a-go-go K+ channel to autonomously prolong fin outgrowth

2019 ◽  
Author(s):  
Scott Stewart ◽  
Heather K. Le Bleu ◽  
Gabriel A. Yette ◽  
Astra L. Henner ◽  
Amy E. Robbins ◽  
...  
Keyword(s):  
Ectopic Expression ◽  
Positional Information ◽  
K Channel ◽  
Chromosome 2 ◽  
Fin Regeneration ◽  
Shape Characteristic ◽  
Small Molecule Inhibition ◽  
Maximal Growth Rate ◽  
Fish Fins ◽  
In Cis

ABSTRACTOrgans stop growing to achieve the size and shape characteristic of the species and in scale with the animal’s body. Likewise, regenerating organs sense injury extents to instruct appropriate replacement growth. Fish fins exemplify both phenomena through their tremendous diversity of form and remarkably robust regeneration. The classic zebrafish mutant longfin develops and regenerates dramatically elongated fins and underlying bony ray skeleton. Here, we show longfin mutant chromosome 2 overexpresses kcnh2a, a voltage-gated potassium channel related to human ether-a-go-go. Genetic disruption of kcnh2a in cis rescues the dominant longfin eponymous phenotype, indicating longfin is a regulatory allele of kcnh2a. We find regenerative fin overgrowth in longfin is characterized by a prolonged outgrowth period rather than increased maximal growth rate. Accordingly, small molecule inhibition of Kcnh2a during late but not early stages of fin regeneration fully suppresses longfin fin overgrowth. Blastula stage transplantations show longfin-expressed kcnh2a acts tissue autonomously in the fin intra-ray mesenchymal lineage, where it is concordantly ectopically expressed. We use temporal delivery of FK506 to show the Ca2+-dependent phosphatase calcineurin likewise entirely acts late in regeneration to attenuate the fin outgrowth period. Epistasis experiments suggest longfin-expressed Kcnh2a inhibits calcineurin signaling to supersede endogenous growth cessation signals. Our results indicate how ion signaling within a growth-determining mesenchyme-lineage controls fin size and morphological variation by tuning outgrowth periods rather than altering positional information.

scholarly journals Cellular diversity of the regenerating caudal fin

2020 ◽  
Vol 6 (33) ◽  
pp. eaba2084
Author(s):  
Yiran Hou ◽  
Hyung Joo Lee ◽  
Yujie Chen ◽  
Jiaxin Ge ◽  
Fujr Osman Ibrahim Osman ◽  
...  
Keyword(s):  
State Transitions ◽  
Specific Cell ◽  
Caudal Fin ◽  
Wound Site ◽  
Fin Regeneration ◽  
Differentiated Cells ◽  
Mesenchymal Differentiation ◽  
Cell Type Specific ◽  
Cell Transcriptome ◽  
Single Cell Transcriptome

Zebrafish faithfully regenerate their caudal fin after amputation. During this process, both differentiated cells and resident progenitors migrate to the wound site and undergo lineage-restricted, programmed cellular state transitions to populate the new regenerate. Until now, systematic characterizations of cells comprising the new regenerate and molecular definitions of their state transitions have been lacking. We hereby characterize the dynamics of gene regulatory programs during fin regeneration by creating single-cell transcriptome maps of both preinjury and regenerating fin tissues at 1/2/4 days post-amputation. We consistently identified epithelial, mesenchymal, and hematopoietic populations across all stages. We found common and cell type–specific cell cycle programs associated with proliferation. In addition to defining the processes of epithelial replenishment and mesenchymal differentiation, we also identified molecular signatures that could better distinguish epithelial and mesenchymal subpopulations in fish. The insights for natural cell state transitions during regeneration point to new directions for studying this regeneration model.

scholarly journals Thyroid hormone regulates proximodistal identity in the fin skeleton

2020 ◽  
Author(s):  
Yinan Hu ◽  
Melody Harper ◽  
Benjamin Acosta ◽  
Joan Donahue ◽  
Hoa Bui ◽  
...  
Keyword(s):  
Gene Expression ◽  
Thyroid Hormone ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Developmental Pathways ◽  
Skeletal Patterning ◽  
Fin Ray ◽  
Fin Rays ◽  
Fish Fins ◽  
Fin Length

AbstractAcross the ∼30,000 species of ray-finned fish, fins show incredible diversity in overall shape and in the patterning of the supportive bony rays. Fin length mutant zebrafish have provided critical insights into the developmental pathways that regulate relative fin size. However, the processes that govern skeletal patterning along the proximodistal axis of the fin have remained less well understood. Here, we show that thyroid hormone regulates proximodistal identity of fin rays, distalizing gene expression profiles, morphogenetic processes during outgrowth, and ultimate morphology of the fin. This role for thyroid hormone in specifying proximodistal identity appears conserved between development and regeneration, in all the fins, and between species. We demonstrate that proximodistal identity is regulated independently from pathways that determine size, and we show that modulating proximodistal patterning relative to growth can recapitulate the spectrum of fin ray diversity found in nature.

scholarly journals Mathematical modeling with single-cell sequencing data

2019 ◽  
Author(s):  
Heyrim Cho ◽  
Russell C. Rockne
Keyword(s):  
Mathematical Modeling ◽  
Mathematical Models ◽  
Single Cell ◽  
Myeloid Leukemia ◽  
State Transitions ◽  
Sequencing Data ◽  
Modeling Framework ◽  
Single Cell Sequencing ◽  
Cell State ◽  
Compare And Contrast

AbstractSingle-cell sequencing technologies have revolutionized molecular and cellular biology and stimulated the development of computational tools to analyze the data generated from these technology platforms. However, despite the recent explosion of computational analysis tools, relatively few mathematical models have been developed to utilize these data. Here we compare and contrast two approaches for building mathematical models of cell state-transitions with single-cell RNA-sequencing data with hematopoeisis as a model system; by solving partial differential equations on a graph representing discrete cell state relationships, and by solving the equations on a continuous cell state-space. We demonstrate how to calibrate model parameters from single or multiple time-point single-cell sequencing data, and examine the effects of data processing algorithms on the model calibration and predictions. As an application of our approach, we demonstrate how the calibrated models may be used to mathematically perturb normal hematopoeisis to simulate, predict, and study the emergence of novel cell types during the pathogenesis of acute myeloid leukemia. The mathematical modeling framework we present is general and can be applied to study cell state-transitions in any single-cell genome sequencing dataset.Author summaryHere we compare and contrast graph- and continuum-based approaches for constructing mathematical models of cell state-transitions using single-cell RNA-sequencing data. Using two publicly available datasets, we demonstrate how to calibrate mathematical models of hematopoeisis and how to use the models to predict dynamics of acute myeloid leukemia pathogenesis by mathematically perturbing the process of cellular proliferation and differentiation. We apply these modeling approaches to study the effects of perturbing individual or sets of genes in subsets of cells, or by modeling the dynamics of cell state-transitions directly in a reduced dimensional space. We examine the effects of different graph abstraction and trajectory inference algorithms on calibrating the models and the subsequent model predictions. We conclude that both the graph- and continuum-based modeling approaches can be equally well calibrated to data and discuss situations in which one method may be preferable over the other. This work presents a general mathematical modeling framework, applicable to any single-cell sequencing dataset where cell state-transitions are of interest.

scholarly journals The Fish Family Poeciliidae as a Model to Study the Evolution and Diversification of Regenerative Capacity in Vertebrates

2021 ◽  
Vol 9 ◽  
Author(s):  
Diego Safian ◽  
Geert F. Wiegertjes ◽  
Bart J. A. Pollux
Keyword(s):  
Molecular Mechanisms ◽  
Reproductive Traits ◽  
Model System ◽  
Animal Kingdom ◽  
Regenerative Capacity ◽  
Fish Family ◽  
Fin Regeneration ◽  
New Model ◽  
Fish Fins ◽  
Livebearing Fish

The capacity of regenerating a new structure after losing an old one is a major challenge in the animal kingdom. Fish have emerged as an interesting model to study regeneration due to their high and diverse regenerative capacity. To date, most efforts have focused on revealing the mechanisms underlying fin regeneration, but information on why and how this capacity evolves remains incomplete. Here, we propose the livebearing fish family Poeciliidae as a promising new model system to study the evolution of fin regeneration. First, we review the current state of knowledge on the evolution of regeneration in the animal kingdom, with a special emphasis on fish fins. Second, we summarize recent advances in our understanding of the mechanisms behind fin regeneration in fish. Third, we discuss potential evolutionary pressures that may modulate the regenerative capacity of fish fins and propose three new theories for how natural and sexual selection can lead to the evolution of fin regeneration: (1) signaling-driven fin regeneration, (2) predation-driven fin regeneration, and (3) matrotrophy-suppressed fin regeneration. Finally, we argue that fish from the family Poeciliidae are an excellent model system to test these theories, because they comprise of a large variety of species in a well-defined phylogenetic framework that inhabit very different environments and display remarkable variation in reproductive traits, allowing for comparative studies of fin regeneration among closely related species, among populations within species or among individuals within populations. This new model system has the potential to shed new light on the underlying genetic and molecular mechanisms driving the evolution and diversification of regeneration in vertebrates.

scholarly journals Changes in the ordering of lipids in the membrane of Dunaliella in response to osmotic-pressure changes. An e.s.r. study

1983 ◽  
Vol 213 (1) ◽  
pp. 131-136 ◽  
Author(s):  
C C Curtain ◽  
F D Looney ◽  
D L Regan ◽  
N M Ivancic
Keyword(s):  
Osmotic Pressure ◽  
Solute Concentration ◽  
Short Term ◽  
Size And Shape ◽  
Head Groups ◽  
Nacl Concentration ◽  
Original Size ◽  
Sudden Decrease ◽  
Pressure Changes ◽  
In Cells

Changes in the ordering and motion of lipids in response to changes in the external solute concentration have been studied by using the 5-nitroxide stearate (5NS) and 16-nitroxide stearate (16NS) spin probes in the plasma membrane of the halotolerant unicellular alga Dunaliella salina. Increases in ordering of the 5NS probe and decreases in motion of the 16NS probe were observed in cells equilibrated over 18 h at increasing NaCl concentrations. These changes probably resulted from the influence of the high NaCl concentration on the charged phospholipid head groups of the membrane. A short-term (less than 100 min) decrease in the order parameter, S, of the 5NS probe was observed for cells swollen by exposure to a sudden decrease of NaCl concentration from 5.0 to 2.5 M. After 100 min the value of S for 5NS was close to the value obtained in cells that had been equilibrated in 2.5 M-NaCl for 18 h. Since the cells had regained their original size and shape by 100 min it was assumed that the short-term decrease in S was associated with the swelling. A similar result was obtained when the cells were suddenly changed from 3.0 M- to 1.5 M-sorbitol. Conversely, an increase in S was observed for cells shrunk when the external solute concentration was doubled from 1.5 M- to 3.0 M-NaCl. As the cells regained their original size and shape the value of S decreased to the value observed in cells that had been equilibrated in 3.0 M-NaCl for 18 h. It is suggested that the changes in S are related to the movement of lipid into or out of a reservoir of membrane material as the membrane shrinks or expands. This movement of lipid maintains the tension of the membrane below the value at which it is disrupted. Such changes in lipid ordering could provide a mechanism whereby information about external osmotic-pressure changes is transmitted across the cell wall.

Mathematical Modeling and Experimental Investigations of Crystallization and Recrystallization Processes to Achieve Targeted Polymorphs and Crystal Size and Shape Distributions

2017 ◽  
pp. 63-85
Author(s):  
Paul Redner ◽  
Nebahat Degirmenbasi ◽  
Ralph Schefflan ◽  
Eileen Heider ◽  
Mark Mezger ◽  
...  
Keyword(s):  
Mathematical Modeling ◽  
Crystal Size ◽  
Experimental Investigations ◽  
Size And Shape

scholarly journals Transcriptional components of anteroposterior positional information during zebrafish fin regeneration

Development ◽  
2013 ◽  
Vol 140 (18) ◽  
pp. 3754-3764 ◽  
Author(s):  
G. Nachtrab ◽  
K. Kikuchi ◽  
V. A. Tornini ◽  
K. D. Poss
Keyword(s):  
Positional Information ◽  
Fin Regeneration

scholarly journals longfin causes cis-ectopic expression of the kcnh2a ether-a-go-go K+ channel to autonomously prolong fin outgrowth

Development ◽  
2021 ◽  
Author(s):  
Scott Stewart ◽  
Heather K. Le Bleu ◽  
Gabriel A. Yette ◽  
Astra L. Henner ◽  
Amy E. Robbins ◽  
...  
Keyword(s):  
Ectopic Expression ◽  
Positional Information ◽  
Characteristic Size ◽  
K Channel ◽  
Chromosome 2 ◽  
Cell Level ◽  
Chemical Inhibition ◽  
Fish Fins ◽  
In Cis ◽  
Temporal Inhibition

Organs stop growing to achieve a characteristic size and shape in scale with the animal's body. Likewise, regenerating organs sense injury extents to instruct appropriate replacement growth. Fish fins exemplify both phenomena through their tremendous diversity of form and remarkably robust regeneration. The classic zebrafish mutant longfint2 develops and regenerates dramatically elongated fins and underlying ray skeleton. We show longfint2 chromosome 2 overexpresses the ether-a-go-go-related voltage-gated potassium channel kcnh2a. Genetic disruption of kcnh2a in cis rescues longfint2, indicating longfint2 is a regulatory kcnh2a allele. We find longfint2 fin overgrowth originates from prolonged outgrowth periods including by showing Kcnh2a chemical inhibition during late stage regeneration fully suppresses overgrowth. Cell transplantations demonstrate longfint2-ectopic kcnh2a acts tissue autonomously within the fin intra-ray mesenchymal lineage. Temporal inhibition of the Ca2+-dependent phosphatase calcineurin indicates it likewise entirely acts late in regeneration to attenuate fin outgrowth. Epistasis experiments suggest longfint2-expressed Kcnh2a inhibits calcineurin output to supersede growth cessation signals. We conclude ion signaling within the growth-determining mesenchyme lineage controls fin size by tuning outgrowth periods rather than altering positional information or cell-level growth potency.

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