Induction of Vertebrate Regeneration by a Transient Sodium Current

Abstract

Amphibians such as frogs can restore lost organs during development, including the lens and tail. To design biomedical therapies for organ repair, it is necessary to develop a detailed understanding of natural regeneration. Recently, ion transport has been implicated as a functional regulator of regeneration. Whereas voltage-gated sodium channels play a well known and important role in propagating action potentials in excitable cells, we have identified a novel role in regeneration for the ion transport function mediated by the voltage-gated sodium channel, Na V 1.2. A local, early increase in intracellular sodium is required for initiating regeneration following Xenopus laevis tail amputation, and molecular and pharmacological inhibition of sodium transport causes regenerative failure. Na V 1.2 is absent under nonregenerative conditions, but misexpression of human Na V 1.5 can rescue regeneration during these states. Remarkably, pharmacological induction of a transient sodium current is capable of restoring regeneration even after the formation of a nonregenerative wound epithelium, confirming that it is the regulation of sodium transport that is critical for regeneration. Our studies reveal a previously undetected competency window in which cells retain their intrinsic regenerative program, identify a novel endogenous role for Na V in regeneration, and show that modulation of sodium transport represents an exciting new approach to organ repair.

Early bioelectric activities mediate redox-modulated regeneration

“…Re-emerging bioelectric studies are revealing transduction mechanisms. V-ATPase-mediated repolarization of membrane potential (V m ) and voltage-gated Na + channel (VGSC or Na V ) 1.2-mediated sodium influx are necessary for and sufficient to induce X. laevis tadpole tail regeneration (Adams et al, 2007;Tseng et al, 2010). V-ATPase proton efflux activity correlates with regeneration rate and ability in zebrafish caudal fin regeneration (Monteiro et al, 2014).…”

“…Interestingly, redox and bioelectric activities control the expression and activity of signaling pathways, such as Wnt, FGF, BMP and Notch, in addition to cell behaviors, such as proliferation, apoptosis and innervation, which are required for regeneration (Adams et al, 2007;Gauron et al, 2013;Han et al, 2014;Love et al, 2013;Monteiro et al, 2014;Tseng et al, 2010). Redox (ROS) and bioelectric [V m , TEP, electric fields (EF) and J I ] states therefore affect regeneration.…”

Transcriptomic, proteomic, and metabolomic landscape of positional memory in the caudal fin of zebrafish

“…Patterning and size control during development and regeneration are also regulated by bioelectric signaling (52,(71)(72)(73)(74)(75)(76)(77)(78). Mutations in two strains of zebrafish with fin size phenotypes map to genes involved in bioelectric signaling (41,79).…”

Local and long-range endogenous resting potential gradients antagonistically regulate apoptosis and proliferation in the embryonic CNS

“…Such patterns of resting potential within living tissues (bioelectric signals) have been studied in the context of their roles in cell migration and wound healing (Cao et al, 2013, Jaffe, 1979, McCaig et al, 2005, Richard B. Borgens, 1989, Zhao et al, 2006 and have long been proposed to direct growth and form in vivo (Burr, 1932). Bioelectric signals are implicated in vertebrate appendage regeneration , Tseng et al, 2010, cancer initiation and metastasis (Binggeli and Weinstein, 1986b, Blackiston et al, 2011, Brackenbury, 2012, Chernet and Levin, 2013b, Lobikin et al, 2012b, left-right patterning (Aw et al, 2008, Aw et al, 2010, Levin et al, 2002, planarian head induction (Beane et al, 2011, Beane et al, 2013, Marsh and Beams, 1947, and eye and brain formation (Nuckels et al, 2009, Pai et al, 2015, Pai et al, 2012a, Pai et al, 2012b. Thus bioelectric signals have been shown to be important regulators of large-scale patterning and tissue and organ identity (Levin, 2009, Levin, 2013a, Levin and Stevenson, 2012, Tseng and Levin, 2013a.…”