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WIREs Dev Biol
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Wound‐induced cell proliferation during animal regeneration

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Many animal species are capable of replacing missing tissues that are lost upon injury or amputation through the process of regeneration. Although the extent of regeneration is variable across animals, that is, some animals can regenerate any missing cell type whereas some can only regenerate certain organs or tissues, regulated cell proliferation underlies the formation of new tissues in most systems. Notably, many species display an increase in proliferation within hours or days upon wounding. While different cell types proliferate in response to wounding in various animal taxa, comparative molecular data are beginning to point to shared wound‐induced mechanisms that regulate cell division during regeneration. Here, we synthesize current insights about early molecular pathways of regeneration from diverse model and emerging systems by considering these species in their evolutionary contexts. Despite the great diversity of mechanisms underlying injury‐induced cell proliferation across animals, and sometimes even in the same species, similar pathways for proliferation have been implicated in distantly related species (e.g., small diffusible molecules, signaling from apoptotic cells, growth factor signaling, mTOR and Hippo signaling, and Wnt and Bmp pathways). Studies that explicitly interrogate molecular and cellular regenerative mechanisms in understudied animal phyla will reveal the extent to which early pathways in the process of regeneration are conserved or independently evolved. This article is categorized under: Comparative Development and Evolution > Body Plan Evolution Adult Stem Cells, Tissue Renewal, and Regeneration > Regeneration Comparative Development and Evolution > Model Systems
Distribution of regenerative capacities in metazoans. A simplified phylogenetic tree of major animal lineages is shown. Left column: extent of regenerative abilities as documented in the literature (dark blue: whole‐body regeneration, light gray: regeneration limited to specific organs/tissues, Ø: no regeneration). Middle column: checkmark indicates taxa with reported injury‐induced hyper‐proliferation (IIHP) based on H3P and/or thymidine analog incorporation, with quantification of cells and comparison to a noninjured control (asterisks indicate the presence of systemic proliferation). Right column: checkmark indicates clades where genetic tools have been used to study gene function in IIHP
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Shared regulators of injury‐induced hyper‐proliferation (IIHP). The distribution of molecular pathway components involved in IIHP across the major models for animal regeneration is shown. Checkmark indicates presence of functional evidence linking the regulator to the control of IIHP in the context of regeneration in vivo. AiP, apoptosis‐induced proliferation; RA, retinoic acid; NO, nitric oxide; BMP, bone morphogenetic protein; FGF, fibroblast growth factor; HGF, hepatocyte growth factor; Nrg, Neuregulin; mTOR: mechanistic target of rapamycin
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Signaling pathways involved in zebrafish injury‐induced hyper‐proliferation (IIHP) during regeneration of heart and tail fin. Schematics of the molecular regulators of IIHP in two types of injury in zebrafish, larval heart and caudal fin amputation (indicated by red line) are shown. Nrg1, Neuregulin1; Raldh2, retinaldehyde dehydrogenase 2; RAR, retinoic acid receptor; RA, retinoic acid; ErbB2 and ErbB3, receptor tyrosine‐protein kinase erbB‐2, erbB‐3; PI3K, phosphatidylinositol‐3‐kinase; IGF, insulin‐like growth factor; JNK, c‐Jun N‐terminal kinase; mTOR, mechanistic target of rapamycin; ROS, reactive oxygen species; FGF, fibroblast growth factor; FGFR, FGF receptor
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Signaling pathways for regulation of injury‐induced hyper‐proliferation (IIHP) in distantly related animal species. Schematics show the known molecular regulators of IIHP in three distantly related model systems (mouse, planarians, and Hydra, which diverged from their last common ancestor ~650 million years ago). From top to bottom: interstitial stem cell‐based head regeneration in Hydra; neoblast‐based whole‐body regeneration in planarians (integrating studies on Schmidtea mediterranea and Dugesia japonica); satellite cell‐based skeletal muscle regeneration in mouse. Red lines indicate plane of amputation. HGF, hepatocyte growth factor; HGF‐A, HGH‐activator; HGFR, HGF receptor; CREB, cAMP responsive element binding protein; mTORC1, mechanistic target of rapamycin complex 1; CBP, CREB binding protein; SMG‐1, suppressor with morphogenetic effect on genitalia; Akt, RAC‐alpha serine/threonine‐protein kinase; RSK, ribosomal S6 kinase; MAPK, mitogen‐activated protein kinase; NO, nitric oxide; Msx, muscle segment homeobox; h/dpa, hours/days post‐amputation
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Comparative Development and Evolution > Model Systems
Adult Stem Cells, Tissue Renewal, and Regeneration > Regeneration
Comparative Development and Evolution > Body Plan Evolution