title: Serotonergic regulation of melanocyte conversion: A bioelectrically regulated network for stochastic all-or-none hyperpigmentation.
abstract: Experimentally induced depolarization of resting membrane potential in "instructor cells" in Xenopus laevis embryos causes hyperpigmentation in an all-or-none fashion in some tadpoles due to excess proliferation and migration of melanocytes. We showed that this stochastic process involved serotonin signaling, adenosine 3',5'-monophosphate (cAMP), and the transcription factors cAMP response element-binding protein (CREB), Sox10, and Slug. Transcriptional microarray analysis of embryos taken at stage 15 (early neurula) and stage 45 (free-swimming tadpole) revealed changes in the abundance of 45 and 517 transcripts, respectively, between control embryos and embryos exposed to the instructor cell-depolarizing agent ivermectin. Bioinformatic analysis revealed that the human homologs of some of the differentially regulated genes were associated with cancer, consistent with the induced arborization and invasive behavior of converted melanocytes. We identified a physiological circuit that uses serotonergic signaling between instructor cells, melanotrope cells of the pituitary, and melanocytes to control the proliferation, cell shape, and migration properties of the pigment cell pool. To understand the stochasticity and properties of this multiscale signaling system, we applied a computational machine-learning method that iteratively explored network models to reverse-engineer a stochastic dynamic model that recapitulated the frequency of the all-or-none hyperpigmentation phenotype produced in response to various pharmacological and molecular genetic manipulations. This computational approach may provide insight into stochastic cellular decision-making that occurs during normal development and pathological conditions, such as cancer.
authors.affiliation: Biology Department and Center for Regenerative and Developmental Biology, Tufts University, Medford, MA 02155, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Lobikin
authors.affiliation: Department of Biological Sciences, University of Maryland, Baltimore County, Baltimore, MD 21250, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Lobo
authors.affiliation: Biology Department and Center for Regenerative and Developmental Biology, Tufts University, Medford, MA 02155, USA.
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Blackiston
authors.affiliation: Center for Environmental and Human Toxicology and Department of Physiological Sciences, UF Genetics Institute, University of Florida, Gainesville, FL 32611, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Martyniuk
authors.affiliation: Biology Department and Center for Regenerative and Developmental Biology, Tufts University, Medford, MA 02155, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Tkachenko
authors.affiliation: Biology Department and Center for Regenerative and Developmental Biology, Tufts University, Medford, MA 02155, USA. michael.levin@tufts.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Levin
mesh_terms: D000818:Animals; D050882:CREB-Binding Protein / Q000502:physiology; D002465:Cell Movement; D048430:Cell Shape; D003198:Computer Simulation; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D017495:Hyperpigmentation / Q000503:physiopathology*; D007559:Ivermectin / Q000494:pharmacology; D007814:Larva / Q000502:physiology*; D000069550:Machine Learning; D008544:Melanocytes / Q000166:cytology / Q000502:physiology*; D008564:Membrane Potentials / Q000187:drug effects; D008954:Models, Biological; D010902:Pituitary Gland / Q000502:physiology; D055757:SOXE Transcription Factors / Q000502:physiology; D012701:Serotonin / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D012880:Skin Pigmentation / Q000502:physiology*; D013269:Stochastic Processes; D014157:Transcription Factors / Q000502:physiology; D014158:Transcription, Genetic; D029867:Xenopus Proteins / Q000502:physiology; D014982:Xenopus laevis / Q000196:embryology / Q000502:physiology*
chemical_list: C561115:SNAI2 protein, Xenopus; D055757:SOXE Transcription Factors; D014157:Transcription Factors; D029867:Xenopus Proteins; D012701:Serotonin; D007559:Ivermectin; D000242:Cyclic AMP; D050882:CREB-Binding Protein; D017868:Cyclic AMP-Dependent Protein Kinases