Genome‐wide analysis reveals conserved transcriptional responses downstream of resting potential change in Xenopus embryos, axolotl regeneration, and human mesenchymal cell differentiation

Abstract

Endogenous bioelectric signaling via changes in cellular resting potential (V mem ) is a key regulator of patterning during regeneration and embryogenesis in numerous model systems. Depolarization of V mem has been functionally implicated in dedifferentiation, tumorigenesis, anatomical re-specification, and appendage regeneration. However, no unbiased analyses have been performed to understand genome-wide transcriptional responses to V mem change in vivo. Moreover, it is unknown which genes or gene networks represent conserved targets of bioelectrical signaling across different patterning contexts and species. Here, we use microarray analysis to comparatively analyze transcriptional responses to V mem depolarization. We compare the response of the transcriptome during embryogenesis (Xenopus development), regeneration (axolotl regeneration), and stem cell differentiation (human mesenchymal stem cells in culture) to identify common networks across model species that are associated with depolarization. Both subnetwork enrichment and PANTHER analyses identified a number of key genetic modules as targets of V mem change, and also revealed important (well-conserved) commonalities in bioelectric signal transduction, despite highly diverse experimental contexts and species. Depolarization regulates specific transcriptional networks across all three germ layers (ectoderm, mesoderm, and endoderm) such as cell differentiation and apoptosis, and this information will be used for developing mechanistic models of bioelectric regulation of patterning. Moreover, our analysis reveals that V mem change regulates transcripts related to important disease pathways such as cancer and neurodegeneration, which may represent novel targets for emerging electroceutical therapies.

Dynamic membrane depolarization is an early regulator of ependymoglial cell response to spinal cord injury in axolotl

“…Taken together, these observations suggest that Vmem-sensitive changes in cell proliferation are cell type and context specific. A recent study published by Pai et al (2015) supports this idea. This study took a comparative approach to identify conserved and divergent voltage-sensitive signaling pathways in developing Xenopus embryos, axolotl spinal cord regeneration and human mesenchymal stem cell differentiation.…”

“…This study took a comparative approach to identify conserved and divergent voltage-sensitive signaling pathways in developing Xenopus embryos, axolotl spinal cord regeneration and human mesenchymal stem cell differentiation. The authors identified several pathways that were similarly activated across species and across cell types in response to prolonged depolarization (Pai et al, 2015). Interestingly, there were also species/cell type specific responses to prolonged depolarization supporting the idea that changes in Vmem can differentially regulate cellular responses based on developmental context and cell type.…”

Widening control of fin inter‐rays in zebrafish and inferences about actinopterygian fins

“…Gene expression associated to wound‐healing/regeneration defects, the control of tissue size or cell interactions are modulated in developing frog, axolotl and humans under experimental Vmem depolarization (Pai et al. ). As previously proposed, initial hyperpolarization/depolarization would regulate voltage‐sensitive mechanisms that would ultimately regulate signalling pathways, such as FGFR1 or SHH in this study, regulating cellular functions (Sundelacruz et al.…”

Coordinating heart morphogenesis: A novel role for hyperpolarization-activated cyclic nucleotide-gated (HCN) channels during cardiogenesis inXenopus laevis

“…Potentially, channels such as HCN4 change the concentration of specific ionic species, altering not only membrane potential but also the localization, modification state, or interactions of critical transmembrane receptors. Likewise, modulation of resting potential by a variety of ion channels is known to regulate transcription of genes such as Notch 76 and of many other targets conserved from amphibian to human 77 . Many studies have also implicated bioelectrical control of the movement of small molecule signals (such as calcium, butyrate, and serotonin) that transduce voltage changes into second messenger cascades and alterations of transcription 39,78 of numerous downstream targets that are well-conserved among human and amphibian bioelectrical signaling responses 79 …”