Appendage regeneration in anamniotes utilizes genes active during larval‐metamorphic stages that have been lost or altered in amniotes: The case for studying lizard tail regeneration

Abstract

This review elaborates the idea that organ regeneration derives from specific evolutionary histories of vertebrates. Regenerative ability depends on genomic regulation of genes specific to the life-cycles that have differentially evolved in anamniotes and amniotes. In aquatic environments, where fish and amphibians live, one or multiple metamorphic transitions occur before the adult stage is reached. Each transition involves the destruction and remodeling of larval organs that are replaced with adult organs. After organ injury or loss in adult anamniotes, regeneration uses similar genes and developmental process than those operating during larval growth and metamorphosis. Therefore, the broad presence of regenerative capability across anamniotes is possible because generating new organs is included in their life history at metamorphic stages. Soft hyaluronate-rich regenerative blastemas grow in submersed or in hydrated environments, that is, essential conditions for regeneration, like during development. In adult anamniotes, the ability to regenerate different organs decreases in comparison to larval stages and becomes limited during aging. Comparisons of genes activated during metamorphosis and regeneration in anamniotes identify key genes unique to these processes, and include thyroid, wnt and non-coding RNAs developmental pathways. In the terrestrial environment, some genes or developmental pathways for metamorphic transitions were lost during amniote evolution, determining loss of regeneration. Among amniotes, the formation of soft and hydrated blastemas only occurs in lizards, a morphogenetic process that evolved favoring their survival through tail autotomy, leading to a massive although imperfect regeneration of the tail. Deciphering genes activity during lizard tail regeneration would address future attempts to recreate in other amniotes regenerative blastemas that grow into variably completed organs.

Form and Function of the Vertebrate and Invertebrate Blood-Brain Barriers

“…While not having the regenerative capabilities of amphibians, reptiles nonetheless have considerable capacities for regeneration. While the regeneration of gross structures (e.g., limbs, tail) have been studied in reptiles [136], there appears to have been little focus specifically on neural regeneration, and especially of the NVU. In the lizard Gallotia galloti, studies of cellular performance following transection of the optic nerve indicate rapid restoration of key components of the neurovascular barrier within a few weeks [137].…”

Myeloid cell diversification during regenerative inflammation: Lessons from skeletal muscle

“…These vertebrates, typically certain anamniotes, whose life is adapted to the aquatic environment, in particular amphibians with the capacity to regenerate extensively entire organs [ 112 , 23 , 79 ]. One school of thought posits that amphibian regeneration is linked to three things: (1) the transition from water to land via the larval stage and thus having elaborate genetic programs for metamorphosis in which the immune system recognize antigens of larval tissues as not-self and destructs the transitory tadpole organs that are replaced by new organs [ 5 ], (2) regeneration is facilitated by a high level of hydration and hyaluronate content to allow the formation of the blastema [ 4 ] and (3) an underdeveloped or suppressed immune system to allow embryoid tissue to develop and new structures be formed. Thus, the low activity or underdeveloped nature of the immune system, in particular the adaptive arm of it, in anamniotes facilitates organ regeneration since the blastema formed after an injury is tolerated long enough to allow regeneration [ 44 – 46 , 62 ].…”

Introduction to the Study on Regeneration in Lizards as an Amniote Model of Organ Regeneration

“…A subsequent study on the expression of the main genes in regeneration compared to scarring tails confirmed that wnt2b, wnt6, c-myc, egfl6, and arhgap28 are among the main genes stimulating tail regeneration [ 71 ]. The study has continued until today, with the immunodetection of numerous coded proteins in both the tail and limbs (summarized in [ 32 , 72 , 73 , 74 , 75 ]). As a result of the above studies on lizards in comparison to fish and amphibian regeneration genes, I elaborated a new evolutionary explanation for the lack of organ regeneration in terrestrial vertebrates [ 32 , 74 ].…”

“…The study has continued until today, with the immunodetection of numerous coded proteins in both the tail and limbs (summarized in [ 32 , 72 , 73 , 74 , 75 ]). As a result of the above studies on lizards in comparison to fish and amphibian regeneration genes, I elaborated a new evolutionary explanation for the lack of organ regeneration in terrestrial vertebrates [ 32 , 74 ].…”

“…A regenerative blastema forms when a temporary immunosuppression is in place after injury or amputation [ 49 , 73 , 74 , 75 ]. Multiple factors contributed to the origin of an immune-privileged blastema: the production of antimicrobial peptides, synthesis of high levels of hyaluronate, initial production of immature anergic lymphocytes, Tregs lymphocytes, and M2-like macrophages, are all combined characteristics that maintain low inflammation and favor regeneration.…”