Maya Emmons-Bell’s research while affiliated with University of California, Berkeley and other places

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Publications (8)


Figure 1.
Figure 4. The ENaC channel Rpk is required for Hh signal transduction. A-A‴ Immunostaining of Smo protein (red) and full-length Ci (light blue) in discs expressing en-Venus. Smo is expressed at higher levels in the P compartment and in a stripe 5-10 cells wide just anterior to the A-P compartment boundary. White arrowhead indicates cells just anterior to the A-P compartment boundary. B, C Effect of expressing an RNAi against the ENaC channel rpk in the dorsal compartment of the disc using ap-Gal4. Knockdown of Rpk in the dorsal compartment results in decreased accumulation of the Hh signal transducer Smo (B, B 0 ) and the activator form of Ci (B, B″). The expression of ptc, visualized using an anti-Ptc antibody (C), a downstream target gene of Hh signalling, is also diminished. The rpk-RNAi line BL:39053 is used in all panels shown, but the phenotype was validated with a second RNAi line (BL:25847). Data information: All scale bars are 50 µm, except for (A) and (B), where scale bars are 100 µm.
Figure 5.
Figure 6. V mem regulates Smo membrane localization independently of Ptc in the wing imaginal disc. A-B″ Wing discs expressing the channelrhodopsin ChR2 were subjected to 0 min or 25 min of activating light in culture, then fixed and stained for Smo protein. In (B″), the yellow arrowhead indicates dorsoventral compartment boundary, and the white arrowhead indicates anteroposterior compartment boundary. C Quantification of the ratio of mean Smo fluorescence intensity in 25 µm 2 regions in the dorsal anterior compartment compared to the ventral posterior compartment. N = 5 for 0 min discs, n = 9 for 25 min discs, data were compared using an unpaired t-test (***P < 0.001), error bars are standard deviations. Identical analyses were carried out comparing dorsal posterior fluorescence to ventral posterior fluorescence (P = 0.132), dorsal posterior fluorescence to dorsal anterior fluorescence (P = 0.12) and ventral posterior fluorescence to ventral anterior fluorescence (P = 0.36). D-E 0 Discs expressing the red light-activated channelrhodopsin ReaChR under control of ap-Gal4 were raised on a 12-h light/dark cycle, dissected and stained for Smo protein (D, D 0 ) or Ptc protein (E, E 0 ). Data information: Scale bars are 100 µm in all panels except (B″) and (E 0 ), where scale bars are 50 µm.
Membrane potential regulates Hedgehog signalling in the Drosophila wing imaginal disc
  • Article
  • Full-text available

February 2021

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56 Reads

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17 Citations

EMBO Reports

Maya Emmons‐Bell

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Iswar K Hariharan

While the membrane potential of cells has been shown to be patterned in some tissues, specific roles for membrane potential in regulating signalling pathways that function during development are still being established. In the Drosophila wing imaginal disc, Hedgehog (Hh) from posterior cells activates a signalling pathway in anterior cells near the boundary which is necessary for boundary maintenance. Here, we show that membrane potential is patterned in the wing disc. Anterior cells near the boundary, where Hh signalling is most active, are more depolarized than posterior cells across the boundary. Elevated expression of the ENaC channel Ripped Pocket (Rpk), observed in these anterior cells, requires Hh. Antagonizing Rpk reduces depolarization and Hh signal transduction. Using genetic and optogenetic manipulations, in both the wing disc and the salivary gland, we show that membrane depolarization promotes membrane localization of Smoothened and augments Hh signalling, independently of Patched. Thus, membrane depolarization and Hh-dependent signalling mutually reinforce each other in cells immediately anterior to the compartment boundary.

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Fig. 1. Constitutively active Yorkie (Yki CA ) disrupts stable selector gene expression. (A and B) Wild-type (WT) wing imaginal discs; Ci is expressed in anterior compartment, and Ubx is expressed in squamous peripodial cells. (C to C″) Clones expressing activated Yki (UAS-yki CA ). Anterior clone (yellow arrowhead) expresses more Ci; posterior clone (white arrowhead) expresses ectopic Ci and Ubx (C″). Discs with Ci-positive clones: n = 74 of 76. Discs with Ubx-positive clones: n = 23 of 28. (D and D′) Ubx-expressing yki CA clones in the disc proper. (E to E″) Mitotic recombination: yki CA -expressing clones express red fluorescent protein (RFP) and green fluorescent protein (GFP) (white arrowheads), and neighboring twin spots (yellow arrowheads) express neither. (F and G) yki CA clones in the eye disc (F and F′), leg disc [(G) and (G′), yellow arrow], and larval brain [(G) and (G′), white arrow]. CNS, central nervous system. (H) Posterior yki CA marked with GFP expresses Ci in the hinge (white arrowhead) but inconsistently in the pouch (red arrowheads). Anterior clones express more Ci (yellow asterisk). (I to L) nubbin-Gal4, UAS-yki CA does not cause ectopic Ci [(J), marked by GFP, control disc in (I)], but 30A-Gal4 UAS-yki CA does [(L), V5 tag on Yki CA , control disc in (K)], especially in the ventral hinge (arrowhead). (M and M′) ci-lacZ is expressed in posterior clones (white arrowheads), and expression is increased in anterior clones (yellow arrowheads). (N) A posterior yki CA clone with down-regulated En and ectopic Ci expression. (N′) XZ section of a posterior yki CA that has been extruded basally. Anterior is left in all images. Scale bars, 100 m. DAPI, 4′,6-diamidino-2-phenylindole; -Gal, -galactosidase.
Fig. 2. yki CA clones require sd, ban, and tara to disrupt patterning gene expression. (A to I) RNA interference (RNAi) of sd [validated in (A) to (C‴) using anti-Sd] in anterior yki CA clones prevents increased Ci expression (D to F, G to G″, and H to H″) and Ci expression in posterior clones (D to F and I to I″). (J and K) yki CA clones in ban 1 /+ discs (K) are overgrown but express less ectopic Ci [compared to (J)]. (L and M) ban sponge reduces ban microRNA levels. dsRed levels inversely correlate with ban levels. Clones expressing ban sponge express uniformly high dsRed and no ectopic Ci (L). Posterior clones expressing Yki CA and ban sponge show variation in both dsRed and Ci expression (M). High dsRed-expressing posterior clones are smaller and do not express Ci (white arrowheads); low-or no-dsRed clones are overgrown and express Ci (yellow arrowheads). (N and O) Yki CA clones have increased expression of Tara protein (N and N′) and tara1-lacz (O and O′), especially in the hinge (arrowheads). (P) tara RNAi allows overgrowth but reduces Ci expression. (Q) Size of posterior hinge clones of indicated genotypes. yki CA clones in ban 1 /+ discs are not significantly smaller than those in WT discs; yki CA + tara RNAi clones are significantly larger than yki CA clones. (R) Ectopic Ci is observed less often in yki CA clones when ban or tara levels are reduced. White boxes, hinge clones; black boxes, hinge and pouch clones. Statistics: See Materials and Methods. ns, not significant.
Fig. 3. ban and tara in combination induce ectopic patterning gene expression. (A and B) Hinge clones expressing either banD (A and A′) or tara (B and B′) together with yki WT express Ci especially in the ventral hinge. (C) Overexpression of tara in yki CA clones further increases Ci expression. (D and E) Combined expression of ban and tara causes some overgrowth and also Ci expression in posterior clones (D and D′) in increased Ci expression and ectopic En expression in anterior clones (E and E′). (F and F′) Clones expressing yki WT , ban, and tara are more overgrown than yki WT alone or with ban or tara individually and consistently express ectopic Ci in the posterior compartment. (G) A total of 77.3% of posterior clones expressing yki WT , tara, and ban express ectopic Ci, while 34.6% of posterior clones expressing RFP, tara, and ban are Ci positive. (H and H′) yki CA clones (GFP positive) show increased H3K27 trimethylation (H3K27me3; red) (H). This increase is only seen in clones in the hinge, where H3K27me3 is already higher than the rest of the disc (white arrowhead) and not in the pouch (yellow arrowhead). (H′) Increased H3K27me3 coincides with ectopic Ci expression. (I and I′) yki CA clones show decreased Pc-mediated repression of a Polycomb-responsive element from the bxd locus linked to a lacZ reporter (green). Yki CA was tagged with V5. Statistics: See Materials and Methods.
Fig. 4. yki CA clones activate a developmental signaling cascade. (A) yki CA clones that express Ci also express Ptc (A′) and dpp-lacZ (B′) at clone margin and have increased pMAD near clones (C′). Control discs without yki CA clones are shown in (A) to (C). (D and E) yki CA clones cause nonautonomous overgrowth in neighboring WT tissue. The TIE-DYE system has three independent FLP-out transgenes that express Gal4, GFP, and lacZ. Clones might express none of these or any combination of these depending on the number of FLP-out events in founder cells. Gal4-expressing clones express UAS-yki CA and are visualized with anti-V5. Neutral GFP-expressing clones are shown in green, and lacZ-expressing clones are shown in blue. Arrowheads indicate two unusually large GFP-positive WT clones that are immediately adjacent to overgrown Yki CA -expressing clones (red). (F and G) Knockdown of dpp in yki CA clones. In these discs, neutral clones adjacent to yki CA clones are not as overgrown (arrowheads). (H) Quantification of size of neutral clones directly adjacent to Gal4-expressing clones [expressing UAS-yki CA (neutral clone, n = 52), UAS-yki CA and UAS-dpp RNAi (neutral clone, n = 184), or UAS-RFP (neutral clone, n = 22)]. (I) Model: Yki CA causes changes in selector gene expression in the posterior compartment via up-regulation of ban and tara. As a result of heterotypic interactions at clone boundaries, ectopic organizing centers are created resulting in the production of morphogens (e.g., Dpp), as well as extrusion of yki CA tissue. Statistics: See Materials and Methods.
The Hippo pathway coactivator Yorkie can reprogram cell fates and create compartment-boundary–like interactions at clone margins

December 2020

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113 Reads

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5 Citations

Science Advances

During development, tissue-specific patterns of gene expression are established by transcription factors and then stably maintained via epigenetic mechanisms. Cancer cells often express genes that are inappropriate for that tissue or developmental stage. Here, we show that high activity levels of Yki, the Hippo pathway coactivator that causes overgrowth in Drosophila imaginal discs, can also disrupt cell fates by altering expression of selector genes like engrailed ( en ) and Ultrabithorax ( Ubx ). Posterior clones expressing activated Yki can down-regulate en and express an anterior selector gene, cubitus interruptus ( ci ). The microRNA bantam and the chromatin regulator Taranis both function downstream of Yki in promoting ci expression. The boundary between Yki-expressing posterior clones and surrounding wild-type cells acquires properties reminiscent of the anteroposterior compartment boundary; Hedgehog signaling pathway activation results in production of Dpp. Thus, at least in principle, heterotypic interactions between Yki-expressing cells and their neighbors could activate boundary-specific signaling mechanisms.


Membrane potential regulates Hedgehog signaling and compartment boundary maintenance in the Drosophila wing disc

June 2020

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47 Reads

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1 Citation

The Drosophila wing imaginal disc is composed of two lineage-restricted populations of cells separated by a smooth boundary. Hedgehog (Hh) from posterior cells activates a signaling pathway in anterior cells near the boundary which is necessary for boundary maintenance. Here, we show that membrane potential is patterned in the wing disc. Anterior cells near the boundary, where Hh signaling is most active, are more depolarized than posterior cells across the boundary. Elevated expression of the ENaC channel Ripped Pocket (Rpk), observed in these anterior cells, requires Hh. Antagonizing Rpk reduces depolarization and disrupts the compartment boundary. Using genetic and optogenetic manipulations, we show that membrane depolarization promotes membrane localization of Smoothened and augments Hh signaling. Thus, membrane depolarization and Hh-dependent signaling mutually reinforce each other in this region. Finally, clones of depolarized cells survive preferentially in the anterior compartment and clones of hyperpolarized cells survive preferentially in the posterior compartment.


Figure 1. Long-term Exposure to BaCl 2 Results in Degeneration of Anterior Tissues and Subsequent Regeneration of Structures That Are Resistant to BaCl 2 (A) Whole D. japonica worms after treatment in 1 mM BaCl 2 . (a) Normal worms before treatment. (b) Within 72 h of exposure to BaCl 2 , the anterior tissues of the planarian degrade and the head deprogresses. This occurs in 83% of worms, SD = 12%. Degeneration occurs through a contraction of tissue at the base of the wound, minimizing tissue loss. (c) After 15 days in BaCl 2 , D. japonica form a blastema and begin to regrow a head. (d) By 37 days of treatment, a new, BaCl 2 -insensitive head has formed and the worm is phenotypically normal. (a'-d') 200x zoomed in images of the anterior portion of the worms shown in (a)-(d). Scale bar 0.5 mm. Results representative of three independent biological replicates, N > 50 for each replicate. (B) (a) D. japonica worm after 35 days of BaCl 2 treatment. This worm has degenerated and regenerated a head and is now insensitive to BaCl 2 . (b) D. japonica worms are then placed in water for 30 days with no obvious morphological effect. (c) However, upon 24 h of a second BaCl 2 treatment, the head degenerates. (a'-c') 200x zoomed in images of the anterior portion of the worms shown in (a)-(c). Scale bar 0.5 mm. Results representative of three independent biological replicates, N > 50 for each replicate.
Figure 2. Possible Mechanism of BaCl 2 -induced Head Degradation Via Excitotoxicity, and Subsequent Adaptation (A) Pathway Studio v10.0 was used to perform pathway analysis of RNA-seq data for (a) anion transport and (b) transmission of nerve impulse, two pathways critical to deprogression and regeneration of the planaria head. Tables S6A and S6B contain details of all of the components listed here. (B) qPCR validation of two transcripts identified as upregulated in the RNA-seq-(a) Dj-TRPMa and (b) Slc2a1. Points represent levels for individual worms normalized to GAPDH. Line indicates median. Unpaired t tests were performed to assess significance, **p < .01, *p < .05, n = 3 for each condition. (C) Proposed regulatory networks detailing (a) normal/untreated state, (b) the main excitotoxicity-related feedback induced by BaCl 2 , and (c) proposed adaptations to BaCl 2 treatment. Red lines with flat endpoints show an inhibitory/ downregulation relationship, whereas blue lines with circular endpoints show an activating/upregulatory relationship. Under normal conditions, K + channels hyperpolarize the cell to regulate membrane excitability and therefore maintain an open state of Ca V channels and upregulate glutamate signaling (a). Ba 2+ is proposed to induce excitotoxicity in neurons by blocking K + channels, leading to significant V mem depolarization, which activates voltage-gated Ca 2+ channels (Ca V )
Figure 3. Visualization of Relative Membrane Potential in WT and BaCl 2 -treated D. japonica Flatworms (A) Voltage-sensitive dye was used to determine pattern of resting potentials in planaria. White arrowheads indicate the anterior of the worm. Images are pseudocolored to allow for ease of visualization of depolarization patterns, but worms were imaged in the same frame so as not to confound data after pseudocoloring, and all image analysis was done using raw un-colored images. (a) Untreated D. japonica flatworm imaged with DiBAC 4 (3) dye. (b) D. japonica flatworm imaged with DiBAC 4 (3) dye after 30 min in BaCl 2 . Scale bars, 0.5 mm. (B) Quantification of average pixel intensities in untreated and BaCl 2 -treated worms. Bars represent mean G SD. Welch's unpaired t test, ***p = 0.00002. See also Figure S1.
Figure 4. Targeting Ion Channels Allows Modulation of Degeneration and Adaptation (A) A variety of drugs targeting ion channels were used to test our excitotoxicity hypothesis. (a and b) D. japonica worm before treatment (a) and after 2 days in water (b). (c and d) Planaria treated with 1 mM BaCl 2 for 0 h (c) show no phenotype, but after 48 h, the head deprogresses (d). (e and f) Planaria in dopamine agonist bromocriptine (0.5 mM) and 1 mM BaCl 2 solution for 0 (e) and 2 days (f). Bromocriptine is able to prevent head degeneration upon exposure to BaCl 2 in 74% of worms (f). (g) exposure to BaCl 2 and calcium-activated chloride channel blocker NPPB (5 mM) has no effect at the time of treatment, but within 2 days (h) NPPB has prevented head degeneration in 84% of worms. (i and j) Calcium-activated chloride channel blocker Niflumic acid (1.24 mM) exposure in combination with BaCl 2 has no effect at 0 days (i) but prevents head degeneration in 92% of worms within 2 days (j). (k and l) L-type calcium channel blocker nicardipine hydrochloride (2.5 mM) treatment in combination with BaCl 2 has no effect at the time of treatment (k) but prevents head degeneration in 78% of worms within 2 days (l). Scale bars, 0.5 mm. (m) Prevalence of head degeneration phenotype with each of the drug treatments listed in (e-l). The overwhelming majority of worms with head degeneration in the BaCl 2 -treated worms are replaced with the majority of worms not experiencing head degeneration when treated with ion channel modulators. (B) Resensitization of worms to BaCl 2 . BaCl 2 -adapted D. japonica worms in (a) water, (b) water with 100 mM AMTB hydrochloride, or (c) water with BaCl 2 do not induce head degeneration in BaCl 2 -adapted worms. (d) However, treatment with AMTB (100 mM) in addition to further treatment with BaCl 2 induced head degeneration within 1.5 h. Scale bars, 0.5 mm. (e) Prevalence of head degeneration phenotypes in BaCl 2 -adapted, BaCl 2 -treated planaria with or without AMTB treatment, as shown in (c) and (d). Treatment with AMTB resulted in a near-complete change from normal heads to fully degenerated heads. See also Figure S2.
Figure S2. Drug treatment alone does not affect planaria, Related to Figure 4. (A) Exposure to Bromocriptine (a,b), NPPB (c,d), Niflumic acid (e,f), or Nicardipine (g,h) for 2 days had no observable effect on D. japonica morphology.
Regenerative Adaptation To Electrochemical Perturbation In Planaria: A Molecular Analysis Of Physiological Plasticity

November 2019

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623 Reads

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26 Citations

iScience

Maya Emmons-Bell

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Fallon Durant

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Angela Tung

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[...]

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Anatomical homeostasis results from dynamic interactions between gene expression, physiology, and the external environment. Owing to its complexity, this cellular and organism-level phenotypic plasticity is still poorly understood. We establish planarian regeneration as a model for acquired tolerance to environments that alter endogenous physiology. Exposure to barium chloride (BaCl2) results in a rapid degeneration of anterior tissue in Dugesia japonica. Remarkably, continued exposure to fresh solution of BaCl2 results in regeneration of heads that are insensitive to BaCl2. RNA-seq revealed transcriptional changes in BaCl2-adapted heads that suggests a model of adaptation to excitotoxicity. Loss-of-function experiments confirmed several predictions: blockage of chloride and calcium channels allowed heads to survive initial BaCl2 exposure, inducing adaptation without prior exposure, whereas blockade of TRPM channels reversed adaptation. Such highly adaptive plasticity may represent an attractive target for biomedical strategies in a wide range of applications beyond its immediate relevance to excitotoxicity preconditioning.


Physiological inputs regulate species-specific anatomy during embryogenesis and regeneration

July 2016

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81 Reads

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73 Citations

Communicative & Integrative Biology

A key problem in evolutionary developmental biology is identifying the sources of instructive information that determine species-specific anatomical pattern. Understanding the inputs to large-scale morphology is also crucial for efforts to manipulate pattern formation in regenerative medicine and synthetic bioengineering. Recent studies have revealed a physiological system of communication among cells that regulates pattern during embryogenesis and regeneration in vertebrate and invertebrate models. Somatic tissues form networks using the same ion channels, electrical synapses, and neurotransmitter mechanisms exploited by the brain for information-processing. Experimental manipulation of these circuits was recently shown to override genome default patterning outcomes, resulting in head shapes resembling those of other species in planaria and Xenopus. The ability to drastically alter macroscopic anatomy to that of other extant species, despite a wild-type genomic sequence, suggests exciting new approaches to the understanding and control of patterning. Here, we review these results and discuss hypotheses regarding non-genomic systems of instructive information that determine biological growth and form.



Gap Junctional Blockade Stochastically Induces Different Species-Specific Head Anatomies in Genetically Wild-Type Girardia dorotocephala Flatworms

November 2015

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231 Reads

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103 Citations

International Journal of Molecular Sciences

The shape of an animal body plan is constructed from protein components encoded by the genome. However, bioelectric networks composed of many cell types have their own intrinsic dynamics, and can drive distinct morphological outcomes during embryogenesis and regeneration. Planarian flatworms are a popular system for exploring body plan patterning due to their regenerative capacity, but despite considerable molecular information regarding stem cell differentiation and basic axial patterning, very little is known about how distinct head shapes are produced. Here, we show that after decapitation in G. dorotocephala, a transient perturbation of physiological connectivity among cells (using the gap junction blocker octanol) can result in regenerated heads with quite different shapes, stochastically matching other known species of planaria (S. mediterranea, D. japonica, and P. felina). We use morphometric analysis to quantify the ability of physiological network perturbations to induce different species-specific head shapes from the same genome. Moreover, we present a computational agent-based model of cell and physical dynamics during regeneration that quantitatively reproduces the observed shape changes. Morphological alterations induced in a genomically wild-type G. dorotocephala during regeneration include not only the shape of the head but also the morphology of the brain, the characteristic distribution of adult stem cells (neoblasts), and the bioelectric gradients of resting potential within the anterior tissues. Interestingly, the shape change is not permanent; after regeneration is complete, intact animals remodel back to G. dorotocephala-appropriate head shape within several weeks in a secondary phase of remodeling following initial complete regeneration. We present a conceptual model to guide future work to delineate the molecular mechanisms by which bioelectric networks stochastically select among a small set of discrete head morphologies. Taken together, these data and analyses shed light on important physiological modifiers of morphological information in dictating species-specific shape, and reveal them to be a novel instructive input into head patterning in regenerating planaria.


Citations (5)


... T cell expansion and functional development depend on adaptive electric and metabolic changes, maintaining electrolyte balances, and appropriate nutrient uptake. The negative charge of the plasma membrane, ion channel expression pattern, and function are key characteristics associated with (Blackiston et al., 2009;Emmons-Bell and Hariharan, 2021;Kiefer et al., 1980;Monroe and Cambier, 1983;Sundelacruz et al., 2009). The electrolytes and nutrients, including amino acids, metabolites, and small peptides transported through ion channels and nutrient transporters, are also regulators and signaling agents impacting the choice of cellular metabolic pathways and functional outcomes (Hamill et al., 2020). ...

Reference:

Neurotrophic factor Neuritin modulates T cell electrical and metabolic state for the balance of tolerance and immunity
Membrane potential regulates Hedgehog signalling in the Drosophila wing imaginal disc

EMBO Reports

... However, the depletion of Mask in wing imaginal discs did not show any significant change in levels of H3K27ac and H3K27me3 ( Supplementary Fig. 6). This could also be explained due to robust regulatory control and crosstalk between different signaling pathways associated with wing morphogenesis thus making the subtle differences in the levels of H3K27ac and H3K27me3 in posterior and anterior compartments difficult to detect through immunostaining (Joanna et al., 2020). ...

The Hippo pathway coactivator Yorkie can reprogram cell fates and create compartment-boundary–like interactions at clone margins

Science Advances

... By placing the cells in a different environment, removing certain developmental constraints rather than by adding new traits to cells, engineers allow them to reset their multicellularity. Cells placed in these unusual situations can identify solutions to new challenges not present in their evolutionary history (Emmons-Bell et al., 2019). Indeed, xenobots showed solutions to problems that are not known yet in life that evolved without the engineering in synthetic morphogenesis. ...

Regenerative Adaptation To Electrochemical Perturbation In Planaria: A Molecular Analysis Of Physiological Plasticity

iScience

... Perturbation of these bioelectric fields by drugs, or manipulation of gap junction protein expression alters anatomy in predicable ways [94]. Most remarkably, establishing suitable resting potentials can guide the regeneration of lost body parts or induce ectopic structures [95]. ...

Physiological inputs regulate species-specific anatomy during embryogenesis and regeneration
  • Citing Article
  • July 2016

Communicative & Integrative Biology

... In planarian flatworms, disruption of gap junction communication during regeneration can lead to double-headed specimens or even worms with characteristics of different planarian species. 9,10 The importance of gap junction connectivity to developmental biology suggests potent applications in synthetic morphology and tissue engineering. ...

Gap Junctional Blockade Stochastically Induces Different Species-Specific Head Anatomies in Genetically Wild-Type Girardia dorotocephala Flatworms
  • Citing Article
  • November 2015

International Journal of Molecular Sciences