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      Serotonergic regulation of melanocyte conversion: A bioelectrically regulated network for stochastic all-or-none hyperpigmentation.

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          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.

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          Author and article information

          Journal
          Sci Signal
          Science signaling
          1937-9145
          1945-0877
          Oct 6 2015
          : 8
          : 397
          Affiliations
          [1 ] Biology Department and Center for Regenerative and Developmental Biology, Tufts University, Medford, MA 02155, USA.
          [2 ] Department of Biological Sciences, University of Maryland, Baltimore County, Baltimore, MD 21250, USA.
          [3 ] Center for Environmental and Human Toxicology and Department of Physiological Sciences, UF Genetics Institute, University of Florida, Gainesville, FL 32611, USA.
          [4 ] Biology Department and Center for Regenerative and Developmental Biology, Tufts University, Medford, MA 02155, USA. michael.levin@tufts.edu.
          Article
          8/397/ra99
          10.1126/scisignal.aac6609
          26443706
          86337b6a-1c3f-4a8c-a0bd-d3c5e8a46caa
          Copyright © 2015, American Association for the Advancement of Science.
          History

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