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Transmembrane potential of GlyCl-expressing instructor cells induces a neoplastic-like conversion of melanocytes via a serotonergic pathway.

Blackiston D, Adams DS, Lemire JM, Lobikin M, Levin M - Dis Model Mech (2010)

Bottom Line: Molecular-genetic depolarization of a sparse, widely distributed set of GlyCl-expressing cells non-cell-autonomously induces a neoplastic-like phenotype in melanocytes: they overproliferate, acquire an arborized cell shape and migrate inappropriately, colonizing numerous tissues in a metalloprotease-dependent fashion.A similar effect was observed in human melanocytes in culture.Depolarization of GlyCl-expressing cells induces these drastic changes in melanocyte behavior via a serotonin-transporter-dependent increase of extracellular serotonin (5-HT).

View Article: PubMed Central - PubMed

Affiliation: Center for Regenerative and Developmental Biology, Biology Department, 200 Boston Avenue, Suite 4600, Tufts University, Medford, MA 02155, USA.

ABSTRACT
Understanding the mechanisms that coordinate stem cell behavior within the host is a high priority for developmental biology, regenerative medicine and oncology. Endogenous ion currents and voltage gradients function alongside biochemical cues during pattern formation and tumor suppression, but it is not known whether bioelectrical signals are involved in the control of stem cell progeny in vivo. We studied Xenopus laevis neural crest, an embryonic stem cell population that gives rise to many cell types, including melanocytes, and contributes to the morphogenesis of the face, heart and other complex structures. To investigate how depolarization of transmembrane potential of cells in the neural crest's environment influences its function in vivo, we manipulated the activity of the native glycine receptor chloride channel (GlyCl). Molecular-genetic depolarization of a sparse, widely distributed set of GlyCl-expressing cells non-cell-autonomously induces a neoplastic-like phenotype in melanocytes: they overproliferate, acquire an arborized cell shape and migrate inappropriately, colonizing numerous tissues in a metalloprotease-dependent fashion. A similar effect was observed in human melanocytes in culture. Depolarization of GlyCl-expressing cells induces these drastic changes in melanocyte behavior via a serotonin-transporter-dependent increase of extracellular serotonin (5-HT). These data reveal GlyCl as a molecular marker of a sparse and heretofore unknown cell population with the ability to specifically instruct neural crest derivatives, suggest transmembrane potential as a tractable signaling modality by which somatic cells can control stem cell behavior at considerable distance, identify a new biophysical aspect of the environment that confers a neoplastic-like phenotype upon stem cell progeny, reveal a pre-neural role for serotonin and its transporter, and suggest a novel strategy for manipulating stem cell behavior.

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A model of melanocyte control by transmembrane potential of cells in the neural crest’s environment. (A) In unperturbed embryos, several classes of ion transporters keep the plasma membrane polarized. This transmembrane potential powers the reuptake of extracellular serotonin through its transporter SERT, resulting in normal melanocyte behavior. (B) By contrast, when the instructor cell population (demarcated by GlyCl expression) is depolarized by targeted modulation of H+, Cl− or K+ channel/pump function, the SERT runs backwards and not only fails to clear the extracellular space of serotonin, but actually exports additional serotonin. The higher serotonin level in the milieu of the neoblasts induces neoplastic-like behavior in melanocytes, as occurs in human cancers. This pathway can be manipulated at a number of points. Consistent with this model, our data show that, although direct serotonin exposure or depolarization of GlyCl-expressing cells can induce hyperpigmentation, the depolarization phenotype can be prevented by overexpression of hyperpolarizing channels or inhibition of SERT. Central features of this model are the regulation of cell behavior by transmembrane potential, regardless of which specific gene product achieves it, and non-cell-autonomous effects of a cell subpopulation specifically instructing, at considerable distance, one derivative of neural crest to undergo the stem-cell-to-neoplastic-cell-like phenotype.
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f8-0040067: A model of melanocyte control by transmembrane potential of cells in the neural crest’s environment. (A) In unperturbed embryos, several classes of ion transporters keep the plasma membrane polarized. This transmembrane potential powers the reuptake of extracellular serotonin through its transporter SERT, resulting in normal melanocyte behavior. (B) By contrast, when the instructor cell population (demarcated by GlyCl expression) is depolarized by targeted modulation of H+, Cl− or K+ channel/pump function, the SERT runs backwards and not only fails to clear the extracellular space of serotonin, but actually exports additional serotonin. The higher serotonin level in the milieu of the neoblasts induces neoplastic-like behavior in melanocytes, as occurs in human cancers. This pathway can be manipulated at a number of points. Consistent with this model, our data show that, although direct serotonin exposure or depolarization of GlyCl-expressing cells can induce hyperpigmentation, the depolarization phenotype can be prevented by overexpression of hyperpolarizing channels or inhibition of SERT. Central features of this model are the regulation of cell behavior by transmembrane potential, regardless of which specific gene product achieves it, and non-cell-autonomous effects of a cell subpopulation specifically instructing, at considerable distance, one derivative of neural crest to undergo the stem-cell-to-neoplastic-cell-like phenotype.

Mentions: A connection between ion transport proteins and pigment cell behavior has been observed in zebrafish, specifically between Kir7.1 and melanosomes (Iwashita et al., 2006), as well as between connexin 41.8 and pigment cells (in a diffusion-reaction patterning system) (Asai et al., 1999; Watanabe et al., 2006). However, our data specifically connect the control of Vmem in one cell population (GlyCl-expressing instructor cells) with migration, morphology and proliferation in another (pigment cells). Indeed, we show that the phenomenon of membrane-voltage-based signaling is even more directly recapitulated in human pigment cells (Fig. 8), suggesting that the previously observed stimulatory effects of bee venom on human melanocytes (Jeon et al., 2007) is due to the ion-channel-targeting properties of its apamin protein component (Seagar et al., 1984). More broadly, the voltage control mechanism might be a plausible candidate for biomedical intervention in the pigmentation disorder vitiligo (Lotti et al., 2008; Whitton et al., 2008), in melanoma (Yamamura et al., 2008a; Yamamura et al., 2008b) and, more broadly, in neurocristopathies (developmental birth defects involving neural crest stem cell derivatives) (Bolande, 1997; De Schepper et al., 2005; Inoue et al., 2007).


Transmembrane potential of GlyCl-expressing instructor cells induces a neoplastic-like conversion of melanocytes via a serotonergic pathway.

Blackiston D, Adams DS, Lemire JM, Lobikin M, Levin M - Dis Model Mech (2010)

A model of melanocyte control by transmembrane potential of cells in the neural crest’s environment. (A) In unperturbed embryos, several classes of ion transporters keep the plasma membrane polarized. This transmembrane potential powers the reuptake of extracellular serotonin through its transporter SERT, resulting in normal melanocyte behavior. (B) By contrast, when the instructor cell population (demarcated by GlyCl expression) is depolarized by targeted modulation of H+, Cl− or K+ channel/pump function, the SERT runs backwards and not only fails to clear the extracellular space of serotonin, but actually exports additional serotonin. The higher serotonin level in the milieu of the neoblasts induces neoplastic-like behavior in melanocytes, as occurs in human cancers. This pathway can be manipulated at a number of points. Consistent with this model, our data show that, although direct serotonin exposure or depolarization of GlyCl-expressing cells can induce hyperpigmentation, the depolarization phenotype can be prevented by overexpression of hyperpolarizing channels or inhibition of SERT. Central features of this model are the regulation of cell behavior by transmembrane potential, regardless of which specific gene product achieves it, and non-cell-autonomous effects of a cell subpopulation specifically instructing, at considerable distance, one derivative of neural crest to undergo the stem-cell-to-neoplastic-cell-like phenotype.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3008964&req=5

f8-0040067: A model of melanocyte control by transmembrane potential of cells in the neural crest’s environment. (A) In unperturbed embryos, several classes of ion transporters keep the plasma membrane polarized. This transmembrane potential powers the reuptake of extracellular serotonin through its transporter SERT, resulting in normal melanocyte behavior. (B) By contrast, when the instructor cell population (demarcated by GlyCl expression) is depolarized by targeted modulation of H+, Cl− or K+ channel/pump function, the SERT runs backwards and not only fails to clear the extracellular space of serotonin, but actually exports additional serotonin. The higher serotonin level in the milieu of the neoblasts induces neoplastic-like behavior in melanocytes, as occurs in human cancers. This pathway can be manipulated at a number of points. Consistent with this model, our data show that, although direct serotonin exposure or depolarization of GlyCl-expressing cells can induce hyperpigmentation, the depolarization phenotype can be prevented by overexpression of hyperpolarizing channels or inhibition of SERT. Central features of this model are the regulation of cell behavior by transmembrane potential, regardless of which specific gene product achieves it, and non-cell-autonomous effects of a cell subpopulation specifically instructing, at considerable distance, one derivative of neural crest to undergo the stem-cell-to-neoplastic-cell-like phenotype.
Mentions: A connection between ion transport proteins and pigment cell behavior has been observed in zebrafish, specifically between Kir7.1 and melanosomes (Iwashita et al., 2006), as well as between connexin 41.8 and pigment cells (in a diffusion-reaction patterning system) (Asai et al., 1999; Watanabe et al., 2006). However, our data specifically connect the control of Vmem in one cell population (GlyCl-expressing instructor cells) with migration, morphology and proliferation in another (pigment cells). Indeed, we show that the phenomenon of membrane-voltage-based signaling is even more directly recapitulated in human pigment cells (Fig. 8), suggesting that the previously observed stimulatory effects of bee venom on human melanocytes (Jeon et al., 2007) is due to the ion-channel-targeting properties of its apamin protein component (Seagar et al., 1984). More broadly, the voltage control mechanism might be a plausible candidate for biomedical intervention in the pigmentation disorder vitiligo (Lotti et al., 2008; Whitton et al., 2008), in melanoma (Yamamura et al., 2008a; Yamamura et al., 2008b) and, more broadly, in neurocristopathies (developmental birth defects involving neural crest stem cell derivatives) (Bolande, 1997; De Schepper et al., 2005; Inoue et al., 2007).

Bottom Line: Molecular-genetic depolarization of a sparse, widely distributed set of GlyCl-expressing cells non-cell-autonomously induces a neoplastic-like phenotype in melanocytes: they overproliferate, acquire an arborized cell shape and migrate inappropriately, colonizing numerous tissues in a metalloprotease-dependent fashion.A similar effect was observed in human melanocytes in culture.Depolarization of GlyCl-expressing cells induces these drastic changes in melanocyte behavior via a serotonin-transporter-dependent increase of extracellular serotonin (5-HT).

View Article: PubMed Central - PubMed

Affiliation: Center for Regenerative and Developmental Biology, Biology Department, 200 Boston Avenue, Suite 4600, Tufts University, Medford, MA 02155, USA.

ABSTRACT
Understanding the mechanisms that coordinate stem cell behavior within the host is a high priority for developmental biology, regenerative medicine and oncology. Endogenous ion currents and voltage gradients function alongside biochemical cues during pattern formation and tumor suppression, but it is not known whether bioelectrical signals are involved in the control of stem cell progeny in vivo. We studied Xenopus laevis neural crest, an embryonic stem cell population that gives rise to many cell types, including melanocytes, and contributes to the morphogenesis of the face, heart and other complex structures. To investigate how depolarization of transmembrane potential of cells in the neural crest's environment influences its function in vivo, we manipulated the activity of the native glycine receptor chloride channel (GlyCl). Molecular-genetic depolarization of a sparse, widely distributed set of GlyCl-expressing cells non-cell-autonomously induces a neoplastic-like phenotype in melanocytes: they overproliferate, acquire an arborized cell shape and migrate inappropriately, colonizing numerous tissues in a metalloprotease-dependent fashion. A similar effect was observed in human melanocytes in culture. Depolarization of GlyCl-expressing cells induces these drastic changes in melanocyte behavior via a serotonin-transporter-dependent increase of extracellular serotonin (5-HT). These data reveal GlyCl as a molecular marker of a sparse and heretofore unknown cell population with the ability to specifically instruct neural crest derivatives, suggest transmembrane potential as a tractable signaling modality by which somatic cells can control stem cell behavior at considerable distance, identify a new biophysical aspect of the environment that confers a neoplastic-like phenotype upon stem cell progeny, reveal a pre-neural role for serotonin and its transporter, and suggest a novel strategy for manipulating stem cell behavior.

Show MeSH
Related in: MedlinePlus