The roles of endogenous retinoid signaling in organ and appendage regeneration

Blum, Nicola; Begemann, Gerrit

doi:10.1007/s00018-013-1303-7

Cited by 11 publications

(7 citation statements)

References 198 publications

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“…The main unresolved question is how the tissue repair mechanism reactivates the regeneration program to generate both structures. The epithelial−mesenchymal interactions are fundamental to the execution of developmental and regenerative programs (Yoshinari & Kawakami 2011;Blum & Begemann 2013;Gemberling et al 2013). Accordingly, the wound epidermis functions not only as a physical barrier to protect the internal fin tissues, but also as an organizer of the underlying blastema.…”

Section: Organizing Factors Of the Blastemamentioning

confidence: 99%

The art of fin regeneration in zebrafish

2015

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The zebrafish fin provides a valuable model to study the epimorphic type of regeneration, whereby the amputated part of the appendage is nearly perfectly replaced. To accomplish fin regeneration, two reciprocally interacting domains need to be established at the injury site, namely a wound epithelium and a blastema. The wound epithelium provides a supporting niche for the blastema, which contains mesenchyme‐derived progenitor cells for the regenerate. The fate of blastemal daughter cells depends on their relative position with respect to the fin margin. The apical compartment of the outgrowth maintains its undifferentiated character, whereas the proximal descendants of the blastema progressively switch from the proliferation program to the morphogenesis program. A delicate balance between self‐renewal and differentiation has to be continuously adjusted during the course of regeneration. This review summarizes the current knowledge about the cellular and molecular mechanisms of blastema formation, and discusses several studies related to the regulation of growth and morphogenesis during fin regeneration. A wide range of canonical signaling pathways has been implicated during the establishment and maintenance of the blastema. Epigenetic mechanisms play a crucial role in the regulation of cellular plasticity during the transition between differentiation states. Ion fluxes, gap‐junctional communication and protein phosphatase activity have been shown to coordinate proliferation and tissue patterning in the caudal fin. The identification of the downstream targets of the fin regeneration signals and the discovery of mechanisms integrating the variety of input pathways represent exciting future aims in this fascinating field of research.

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Section: Organizing Factors Of the Blastemamentioning

confidence: 99%

The art of fin regeneration in zebrafish

2015

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“…Limiting RA concentration, inhibiting RAR signaling, or inhibiting RA metabolism has detrimental effects on limb development in chicks (Roselló-Díez et al, 2011;Stratford et al, 1996), zebrafish (Grandel et al, 2002) and mammals (Dranse et al, 2011;Lohnes et al, 1994;Niederreither et al, 2002;Sandell et al, 2012Sandell et al, , 2007Williams et al, 2009;Yashiro et al, 2004). The role of RA during limb regeneration is less clear (Blum and Begemann, 2013), although several lines of evidence support an active role. RA is present in regenerating limbs (Scadding and Maden, 1994) and RA-reporter axolotls show RA signaling in regenerating limbs (Monaghan and Maden, 2012b).…”

Section: Introductionmentioning

confidence: 99%

Retinoic acid receptor regulation of epimorphic and homeostatic regeneration in the axolotl

et al. 2017

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Salamanders are capable of regenerating amputated limbs by generating a mass of lineage-restricted cells called a blastema. Blastemas only generate structures distal to their origin unless treated with retinoic acid (RA), which results in proximodistal (PD) limb duplications. Little is known about the transcriptional network that regulates PD duplication. In this study, we target specific retinoic acid receptors (RARs) to either PD duplicate (RA treatment or RARγ agonist) or truncate (RARβ antagonist) regenerating limbs. RARE-EGFP reporter axolotls showed divergent reporter activity in limbs undergoing PD duplication versus truncation, suggesting differences in patterning and skeletal regeneration. Transcriptomics identified expression patterns that explain PD duplication, including upregulation of proximal homeobox gene expression and silencing of distal-associated genes, whereas limb truncation was associated with disrupted skeletal differentiation. RARβ antagonism in uninjured limbs induced a loss of skeletal integrity leading to long bone regression and loss of skeletal turnover. Overall, mechanisms were identified that regulate the multifaceted roles of RARs in the salamander limb including regulation of skeletal patterning during epimorphic regeneration, skeletal tissue differentiation during regeneration, and homeostatic regeneration of intact limbs.

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“…The molecular events that underlie this process are not well understood and likely involve global changes in gene expression. One factor that may be critical in this process is a biologically active metabolite of vitamin A, all‐trans retinoic acid (RA) (Maden, , Blum and Begemann ). RA is known to modulate the growth and differentiation of many cell types and is an important morphogenetic molecule in the embryo (Duester, ).…”

Section: Introductionmentioning

confidence: 99%

RARβ2 expression is induced by the down‐regulation of microRNA 133a during caudal spinal cord regeneration in the adult newt

Lepp

Carlone

2014

Developmental Dynamics

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Background: Adult urodele amphibians represent unique model organisms to study spinal cord regeneration. Trauma to the spinal cord induces an ependymal response, activating multipotent neural stem cells that contribute to the redifferentiation of both glia and neurons in the regenerate. The molecular events underlying this ependymal response are not completely understood, but likely involve coordinated global changes in gene expression. MicroRNAs and retinoid signaling are postulated to orchestrate these patterns of gene expression in response to trauma. Our objectives were to determine the roles played by some miRNAs as potential regulators of retinoid signaling in this process. Results: We found that the expression levels of miRNAs 133a, 203, and 124a are dysregulated during the first 21 days post amputation (dpa). Interestingly, these miRNAs are expressed primarily within the ependymoglia. We have shown in vitro that a miR-133a mimic targets the 3' UTR of the newt RARb2 transcript. Importantly, upregulation of this mimic in vivo led to a significant decline in RARb2 protein at 14 dpa and inhibited regeneration. Conclusions: These data are the first to link miRNAs and retinoid signaling during spinal cord regeneration and provide support for miR-133a as an upstream regulator of RARb2 expression in this process. Developmental Dynamics 243:1581-1590,

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The roles of endogenous retinoid signaling in organ and appendage regeneration

Cited by 11 publications

References 198 publications

The art of fin regeneration in zebrafish

The art of fin regeneration in zebrafish

Retinoic acid receptor regulation of epimorphic and homeostatic regeneration in the axolotl

RARβ2 expression is induced by the down‐regulation of microRNA 133a during caudal spinal cord regeneration in the adult newt

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