Bioelectric signaling regulates head and organ size during planarian regeneration

Abstract

SUMMARYA main goal of regenerative medicine is to replace lost or damaged tissues and organs with functional parts of the correct size and shape. But the proliferation of new cells is not sufficient; we will also need to understand how the scale and ultimate form of newly produced tissues are determined. Using the planarian model system, we report that membrane voltage-dependent bioelectric signaling determines both head size and organ scaling during regeneration. RNA interference of the H + ,K + -ATPase ion pump results in membrane hyperpolarization, which has no effect on the amount of new tissue (blastema) that is regenerated yet produces regenerates with tiny 'shrunken' heads and proportionally oversized pharynges. Our data show that this disproportionality results from a lack of the apoptosis required to adjust head and organ size and placement, highlighting apoptotic remodeling as the link between bioelectric signaling and the establishment of organ size during regeneration.

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

“…6iii). While a role of bioelectric signal in regulating apoptosis-proliferation has been shown in determining planarian regeneration (Beane et al, 2013), this is the first account of bioelectric signal (particularly contribution of both local and distant bioelectric signals) controlling the apoptosis-proliferation balance in sculpting the neural tissue in a developing vertebrate embryo.…”

“…In addition to activity-dependent sculpting of neural connections (Kozorovitskiy et al, 2012, Penn andShatz, 1999), the spatial distribution patterns of V mem in developing embryos controls aspects of large-scale morphogenesis of the nervous system, particularly eye and brain (Beane et al, 2013, Pai et al, 2015, Pai et al, 2012a, Pai et al, 2012b. Here we assess the effect of V mem specifically on apoptosis and proliferation within the developing central nervous system (CNS) as it regulates the large-scale morphogenesis of the brain and spinal cord.…”

“…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.…”

Reconsidering regeneration in metazoans: an evo-devo approach

“…The presence of an exoskeleton, as in many ecdysozoan phyla could constrain the regeneration of a body structure just as, for example, it constitutes a limit for the increase of body size in insects (Nijhout and Emlen, 1998). Soft bodied animals, where the histological and cytological structure is more homogeneous could facilitate or restrain the propagation of morphogenetic gradients and bioelectrical signals through voltage gradients across the plasma membrane of cells (Levin, 2012;Levin and Stevenson, 2012;Beane et al, 2013). In fact, among metazoans, the evolution of particular body structures seems to interact at different levels during the regenerative processes.…”

Wnt/Notum spatial feedback inhibition controls neoblast differentiation to regulate reversible growth of the planarian brain

“…As planarians can perform tissue remodeling and blastema formation through periods of starvation, it is possible that regulated autophagy could contribute to these processes (González-Estévez, 2009;González-Estévez et al, 2007). Perturbation of several molecular processes can influence body and organ size in planarians, including bioelectric signaling (Beane et al, 2012), FGF signaling (Cebrià et al, 2002a, JNK signaling (Almuedo-Castillo et al, 2014), TORC1 signaling (González-Estévez et al, 2012b;Peiris et al, 2012;Tu et al, 2012) and insulin-like peptide signaling (Miller and Newmark, 2012). However, there is still a limited understanding of the developmental and molecular events that underlie the attainment and maintenance of appropriate organ size in planarians.…”