Annals of Anatomy 222 (2019) 114–119 Contents lists available at ScienceDirect Annals of Anatomy jou rnal homepage: www.elsevier.com/locate/aanat INVITED REVIEW Organ regeneration evolved in fish and amphibians in relation to metamorphosis: Speculations on a post-embryonic developmental process lost in amniotes after the water to land transition a,b,∗ Lorenzo Alibardi a Comparative Histolab Padova, Italy b Dept Biology Univ Bologna, Italy a r a t i c l e i n f o b s t r a c t Article history: Organ regeneration occurs in anamniotes (fish and amphibians) while is absent in amniotes (reptiles, Received 26 November 2018 birds and mammals). An evolutionary hypothesis is presented to explain the loss of organ regeneration Received in revised form in amniotes. The aquatic life in fish or the initial aquatic and later terrestrial life in amphibians requires 10 December 2018 complex life cycles after embryonic development. One or more larval stages that occupy different ecolog- Accepted 11 December 2018 ical niches are necessary in fish to reach the final adult stage, generally through metamorphosis. This is a post-embryonic process determined by genes that are constitutive of the genome of fish and amphib- Keywords: ians, and that can also be re-utilized during adult life to regenerate injured or lost organs. During the Fish Amphibians adaptation to terrestrial niches, the larval stages disappeared and a direct development evolved with Amniotes the formation of the amniote egg in reptiles and birds or the blastocysts in mammals. The genome for Metamorphosis developing larvae and metamorphosis was therefore eliminated from the life cycle of amniotes. The loss Organ regeneration of genes utilized for metamorphosis determined also the loss of the capability to regenerate organs in Scarring adults, especially of the neural organization of the nervous system. The cellular immune system that in anamniotes was operating in metamorphic destruction of larval tissues, in amniotes became no longer tolerant to embryonic-larval antigens. The loss of genes operating during metamorphosis and presence of intolerant immune cells determined the inability to regenerate organs in amniotes. Efforts of regenerative medicine must overcome these genetic and immune barriers to induce organ regeneration. © 2018 Elsevier GmbH. All rights reserved. Contents 1. Introduction . 114 2. Life cycles of fish, growth and metamorphosis . 115 3. Amphibian life cycles and metamorphosis in relation to the transition to land . 116 4. Loss of metamorphosis in amniotes and direct development . 117 Ackowledgments . 118 References . 118 1. Introduction It was known at least since the experiments of the Italian that also fish can regenerate their appendages, in particular the zoologist L. Spallanzani in 1765, that organ regeneration among caudal fin as discovered by the French naturalist M. Broussonet in vertebrates occurs in newts and salamanders (urodele amphibians) 1786. In comparison to amphibians, studies on fish regeneration but not in other vertebrates (Okada, 1996; Tsonis, 2000; McCusker have been scanty but they indicated some ability to regenerate the et al., 2015; Stocum, 2018). Other poorly known researches found amputated tail (Zanandrea, 1956; Maron, 1960; Bird, 1978; George, 1968). Recently, numerous studies have shown that some species of fish, in particular the teleost zebrafish, can also regenerate various ∗ tissues and organs, sometimes almost like those of salamanders Correspondence to: Department of Biology, University of Bologna, Bologna, Italy. E-mail address: [email protected] (Wagner and Bernard, 1992; Santos-Ruiz et al., 2002; Nakatani https://doi.org/10.1016/j.aanat.2018.12.005 0940-9602/© 2018 Elsevier GmbH. All rights reserved. L. Alibardi / Annals of Anatomy 222 (2019) 114–119 115 et al., 2007; Bockelmann et al., 2009; Cuervo et al., 2012; Yoshinary symmetric fins and later development of asymmetric fins, changes and Kawakami, 2011; Nikiforova and Golikenchov, 2012; Davidson, in the shape and extension of the caudal fin etc. In another relatively 2014; Jazwinska and Sallin, 2015; Rasmussen and Sagasti, 2017). primitive freshwater fish, the garfish Lepisosteus (holosteans), the Among organs known to regenerate with different degrees in fish larva initially develops, among others, adhesive organs, is devoid are the fins, scales, spinal cord, brain regions, optic nerve and eye of scales, possess a temporary long dorsal caudal filament and a parts, intestine, kidney, heart areas, skeleton parts, and others. A different pigmentation pattern from the adult. remarkable example of regeneration is seen in the transected spinal After reproduction in numerous bony fish the fertilized eggs, cord of the lamprey and some cartilaginous and bony fish: after either on the bottom or fluctuating in the sea or in streams of the initial paralysis the fish slowly regains motor coordination and freshwater, are abandoned from their parents and they develop and swimming ability (Maron, 1963; Bernstein, 1988; Lurie and Saltzer, hatch as tiny larvae that during the initial stages of post-embryonic 1991; Ferretti et al., 2003; Tanaka and Ferretti, 2009; Rasmussen life are very different from the adult parent, and occupy a diverse and Sagasti 2016.). Therefore not only amphibians but also numer- ecological and feeding niches (Szarski, 1957; Lagler et al., 1962; ous fish, both anamniotes linked to an aquatic lifestyle, are capable McMenamin and Parichy, 2013; Kipanyula and Maina, 2016). In to regenerate numerous organs nearly completely, recovering part some species, the larvae grow in size but also change shape and or most of their original function (restitutive regeneration). anatomy since their genome is programmed to give rise to different As opposed this remarkable regenerative capability is almost post-embryonic stages that grow with few anatomical traits differ- completely lost in amniotes, namely reptiles, birds and mam- ent from the adults. This occurs in hagfish, trout, catfish, garfish, mals, vertebrates variably adapted to a terrestrial life. The only tuna, codfish, anchovy, etc. In other species such as lamprey, lung- parenchymal organs capable to regenerate in terrestrial vertebrates fish, bowfin, herring, carp, sucker, sunfish, goosefish, mole-fish, are the liver in most amniotes and the tail in lizards, while the anglerfish, rockfish, eel, etc., the larva stage is so different from the seasonal regeneration of the bony horns of cervids appears an adult stage to require one or more intense remodeling phases indi- osteogenic specialization of localized periosteal cells that do not cated as metamorphoses, in order to change dramatically shape really form a blastema (Li et al., 2005; Alibardi, 2010, 2014, 2017a; and physiological adaptations. In some cases the tadpole (larva) Cordero-Espinoza and Hutch, 2018; Seifert and Muneoka, 2018). changes not only internal organs but also the entire external look The adaptation of vertebrates to a terrestrial lifestyle with the in successive periods, and at any change a true process of metamor- evolution of the complexity of the nervous and immune systems phosis occurs (Fig. 1C; Szarski, 1957). Some larval and intermediate somehow determined loss of organ regeneration that is replaced forms of fish are so different, like for the eels or tape-tail fish, that by scarring (Ferguson and O’Kane, 2004; Jazwinska and Sallin, they were initially classified as different species or even families 2015). The present hypothesis, based on the presence of larvae (Johnson et al., 2009). The skin in larvae is often devoid of scales and metamorphosis in the lifecycle of anamniotes, provides a gen- and results smooth and, like the rest of the body features a watery eral biological explanation for the loss of developmental plasticity consistency, similar to that of embryos, and the skeleton is only in amniotes. The present hypothesis may stimulate deep molecu- cartilaginous. This soft consistency of body tissues is also present lar studies on the genes involved in metamorphosis and in organ in all the species that can regenerate organs, as will be reported regeneration in vertebrates. later on. Among bony fish some remarkable changes occur between post- hatched larvae and adults, and they require one or more periods of 2. Life cycles of fish, growth and metamorphosis dramatic body and organ modifications, corresponding to multiple metamorphic phases (exemplified from the eel general cycle shown Life in water, especially in low sea level where vertebrates in Fig. 1C; Szarski, 1957). The case of salmons, where numerous evolved in the Cambrian or Ordovician, about 480 million years anatomical and physiological changes occur from larvae to marine ago (MYA), is very different from life on land. In pre-vertebrate adults and during their return to freshwater, evidences another forms, the limited genome contained all the genes necessary for complex metamorphic life cycle (McMenamin and Parichy, 2013). development and for building the larval forms before reaching These different developmental programs depend from the pres- the adult condition (Fig. 1A; Orton, 1953; Szarski, 1957; Lagler ence of a number of genes that determine the morphogenesis of et al., 1962; McMenamin and Parichy, 2013). Larvae or intermediate some organs, their destruction during metamorphosis, and their developmental forms evolved because the dispersion of develop- following regeneration into modified organs or even new organs. ing embryos in the aquatic environment after fertilization forces For instance, in