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Retinoic Acid Receptors and the Control of Positional Information in the Regenerating Axolotl Limb

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Retinoic Acid Receptors and the Control of Positional Information in the Regenerating Axolotl Limb cells Article Retinoic Acid Receptors and the Control of Positional Information in the Regenerating Axolotl Limb Trey Polvadore and Malcolm Maden * Department of Biology & UF Genetics Institute, University of Florida, Gainesville, FL 32610, USA; polvadore@ufl.edu * Correspondence: malcmaden@ufl.edu Abstract: We know little about the control of positional information (PI) during axolotl limb regener- ation, which ensures that the limb regenerates exactly what was amputated, and the work reported here investigates this phenomenon. Retinoic acid administration changes the PI in a proximal direc- tion so that a complete limb can be regenerated from a hand. Rather than identifying all the genes altered by RA treatment of the limb, we have eliminated many off-target effects by using retinoic acid receptor selective agonists. We firstly identify the receptor involved in this respecification process as RARα and secondly, identify the genes involved by RNA sequencing of the RARα-treated blastemal mesenchyme. We find 1177 upregulated genes and 1403 downregulated genes, which could be identified using the axolotl genome. These include several genes known to be involved in retinoic acid metabolism and in patterning. Since positional information is thought to be a property of the cell surface of blastemal cells when we examine our dataset with an emphasis on this aspect, we find the top canonical pathway is integrin signaling. In the extracellular matrix compartment, we find a MMP and several collagens are upregulated; several cell membrane genes and secretory factors are also upregulated. This provides data for future testing of the function of these candidates in the control of PI during limb regeneration. Keywords: retinoic acid; retinoic acid receptor; RARα; positional information; axolotl; limb regeneration Citation: Polvadore, T.; Maden, M. Retinoic Acid Receptors and the Control of Positional Information in the Regenerating Axolotl Limb. Cells 1. Introduction 2021 10 , , 2174. https://doi.org/ The axolotl (Ambystoma mexicanum), a salamander native to Mexico, is capable of 10.3390/cells10092174 extraordinary feats of regeneration including complete regeneration of severed limbs. Regardless of where the amputation occurs along the proximal–distal (PD; shoulder to Received: 20 July 2021 hand) limb axis, only the missing tissue is regrown. This indicates that cells in the limb Accepted: 19 August 2021 Published: 24 August 2021 blastema, a conical assembly of proliferating cells that will form the regenerated tissue, are somehow aware of their position along the PD axis. This property is reflected in Publisher’s Note: MDPI stays neutral the rule of distal transformation, which states that regeneration can only occur in the with regard to jurisdictional claims in proximal-to-distal direction, as blastema cells can only create cells with an identity more published maps and institutional affil- distal than their own. An amputation between the elbow and wrist, for example, is unable iations. to regenerate a second elbow as those tissues would require more proximal identities. While this phenomenon has been widely studied, the molecular mechanisms that govern the establishment, maintenance, and interpretation of positional information (PI) are still poorly understood. Unlike development, where concentration gradients of extracellular morphogens are Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. considered to be the means by which positional information is encoded, in regeneration, This article is an open access article the cell surface of connective tissue blastemal cells has become the focus of attention. For distributed under the terms and example, when a wrist blastema is grafted proximally to the upper arm level and the limb conditions of the Creative Commons is then amputated through the upper arm, the grafted blastema will move distally as the Attribution (CC BY) license (https:// limb regenerates and then cease moving and integrate at the wrist level from which it creativecommons.org/licenses/by/ originated [1]. When a blastema is cut off from the limb, rotated 180 degrees around the 4.0/). circumferential axis, and placed back on the limb stump, it will frequently de-rotate and Cells 2021, 10, 2174. https://doi.org/10.3390/cells10092174 https://www.mdpi.com/journal/cells Cells 2021, 10, x FOR PEER REVIEW 2 of 17 Cells 2021, 10, 2174 limb regenerates and then cease moving and integrate at the wrist level from which2 of 17it originated [1]. When a blastema is cut off from the limb, rotated 180 degrees around the circumferential axis, and placed back on the limb stump, it will frequently de-rotate and end up in the same position at which it started [2]. When proximal and distal blastemas end up in the same position at which it started [2]. When proximal and distal blastemas are cultured in vitro, proximal blastemas engulf distal blastemas, while blastemas from are cultured in vitro, proximal blastemas engulf distal blastemas, while blastemas from similar positions simply fuse with each other [3], suggesting there is a gradient of cell similar positions simply fuse with each other [3], suggesting there is a gradient of cell adhesion along the PD axis, which is used to interpret positional information through cell adhesion along the PD axis, which is used to interpret positional information through cell surface interactions. surface interactions. AnAn exceptionexception toto thethe rulerule ofof distaldistal transformationtransformation waswas foundfound whenwhen distaldistal blastemasblastemas werewere treatedtreated withwith retinoicretinoic acidacid (RA),(RA), aa derivativederivative ofof vitaminvitamin A,A, andand regeneratedregenerated anan entireentire armarm composedcomposed of all three limb segments (upper (upper arm, arm, forearm, forearm, and and hand). hand). This This respecifi- respeci- ficationcation of of distal distal identity identity to toa proximal a proximal state state by byRA RA was was originally originally seen seen in axolotl in axolotl limbs limbs and andfound found to be to dependent be dependent on both on the both concentration the concentration of RA ofand RA len andgth lengthof treatment of treatment (Figure (Figure1) [4,5].1 )[In an4,5 attempt]. In an to attempt understand to understand the molecular the molecularbasis of respecification basis of respecification,, a subtractive a subtractivescreen was screenperformed was performedbetween untreated between untreatedand RA-treated and RA-treated distal blastemas distal blastemas in the newt in the(Notophtalmus newt (Notophtalmus viridescens viridescens). In accordance). In accordance with the with sugge thested suggested location location of PI, this of PI, screen this screenidentified identified prod1, aprod1 gene, aencoding gene encoding a cell surface a cell surfaceprotein, protein,which was which upregulate was upregulatedd approxi- approximatelymately 15-fold 15-foldafter RA after treatment RA treatment [6]. Further [6]. Further experimentation experimentation showed showed that removing that re- movingProd1 from Prod1 the frommembrane the membrane or treating or cells treating with cellsa blocking with a antibody blocking changed antibody the changed engulf- thement engulfment behavior behaviorof distal ofcells distal, and cells, over and-expression over-expression of prod1 of inprod1 the blastemain the blastema cells trans- cells transformedformed distal distal cells cells into into more more proxima proximall cells cells [7]. [7 ].However, However, the the axolotl axolotl homolog homolog to newtnewt Prod1Prod1 isis notnot membrane-boundmembrane-bound andand doesdoes notnot appearappear toto havehave directdirect effectseffects onon PIPI [[8]8],, soso thethe searchsearch forfor aa positional positional identity identity gene gene in in the the axolotl axolotl continues. continues. Recent Recent studies studies have have identified identi- differentialfied differential gene gene expression expression in the in axolotl the axolotl limb blastemalimb blastema following following RA treatment RA treatment [9], but [9] it, hasbut provenit has proven difficult difficult to parse to positionally parse positionally relevant relevant genes from genes the from many the genes many involved genes in- in RAvolved signaling. in RA signaling. FigureFigure 1. RetinoicRetinoic acid acid induces induces the the proximalization proximalization of regenerating of regenerating tissue tissue and andduplicates duplicates limb limbele- elementsments along along the the PD PD axis. axis. (A ()A Following) Following amputation amputation of of the the axolotl axolotl forelimb forelimb at at the the mid mid-radius/ulna,-radius/ulna, thethe regenerateregenerate (gray) (gray) is is identical identical to to the the tissue tissue lost. lost. If If the the regenerating regenerating limb limb is treated is treated with with retinoic retinoic acid, moreacid, more tissue tissue is regenerated is regenerated and limb and elementslimb elements are duplicated are duplicated (red). (red). Regenerates Regenerates 1 through 1 through 5 depict 5 depict five possibilities, each showing higher levels of duplication caused by increasing concentra- five possibilities, each showing higher levels of duplication caused by increasing concentrations of tions of RA (blue gradient, increasing from left to right). Regenerate 5 shows complete duplication RA (blue gradient, increasing from left to right). Regenerate 5 shows complete duplication of the of the humerus, a result indicative of
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