Unipotent,<i>Atoh1</i>+ progenitors maintain the Merkel cell population in embryonic and adult mice

Wright, Margaret C.; Reed-Geaghan, Erin G.; Bolock, Alexa M.; Fujiyama, Tomoyuki; Hoshino, Mikio; Maricich, Stephen M.

doi:10.1083/jcb.201407101

Cited by 42 publications

(55 citation statements)

References 49 publications

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“…We also tested alternate Merkel-cell markers in anagen, catagen and telogen. We found that 77% of K8-positive Merkel cells expressed the early marker Atoh1-GFP ( N =391 from 5 mice; Figure 2D; Wright et al , 2015). VGLUT2 immunoreactivity, which is found in mature Merkel cells and touch-dome afferents (Haeberle et al , 2004), co-localized with K8 in 96% of Merkel cells ( N =489 from 5 mice; Figure 2E).…”

Section: Resultsmentioning

confidence: 93%

Touch Receptors Undergo Rapid Remodeling in Healthy Skin

Marshall¹,

Clary²,

Baba³

et al. 2016

Cell Reports

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Summary Sensory tissues exposed to the environment, such as skin, olfactory epithelia and taste buds, continuously renew; therefore, peripheral neurons must have mechanisms to maintain appropriate innervation patterns. Although somatosensory neurons regenerate after injury, little is known about how these neurons cope with normal target-organ changes. To elucidate neuronal plasticity in healthy skin, we analyzed the structure of Merkel-cell afferents, which are gentle touch receptors, during skin remodeling that accompanies mouse hair-follicle regeneration. The number of Merkel cells is reduced by 90% and axonal arbors are simplified during active hair growth. These structures rebound within just days. Computational modeling predicts that Merkel-cell changes are probabilistic but myelinated branch stability depends on Merkel-cell inputs. Electrophysiology and behavior demonstrate that tactile responsiveness is less reliable during active growth than in resting skin. These results reveal that somatosensory neurons display structural plasticity at the cost of impairment in the reliability of encoding gentle touch.

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Section: Resultsmentioning

confidence: 93%

Touch Receptors Undergo Rapid Remodeling in Healthy Skin

Marshall¹,

Clary²,

Baba³

et al. 2016

Cell Reports

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“…These data imply the existence of a Merkel cell precursor that gives rise to new Merkel cells. We recently showed that embryonic Merkel cell precursors express Atoh1 and are unipotent (Wright et al, 2015). However, three lines of evidence suggest that ectopic K8+ cells created by ectopic Atoh1 expression are post-mitotic.…”

Section: Discussionmentioning

confidence: 99%

“…Mature Merkel cells do not express keratinocyte markers (Haeberle et al, 2004;Moll et al, 1995;Wright et al, 2015), and we wondered whether ectopic Atoh1 expression in keratinocytes altered normal marker expression in these cells. Four days postinduction, we found no cells that co-expressed Atoh1 and the general keratinocyte marker K14 (Krt14 -Mouse Genome Informatics; Fig.…”

Section: Inducible Atoh1 Expression Produces Ectopic K8+ Cells In Glamentioning

confidence: 99%

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EctopicAtoh1expression drives Merkel cell production in embryonic, postnatal and adult epidermis

et al. 2015

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Merkel cells are mechanosensitive skin cells whose production requires the basic helix-loop-helix transcription factor Atoh1. We induced ectopic Atoh1 expression in the skin of transgenic mice to determine whether Atoh1 was sufficient to create additional Merkel cells. In embryos, ectopic Atoh1 expression drove ectopic expression of the Merkel cell marker keratin 8 (K8) throughout the epidermis. Epidermal Atoh1 induction in adolescent mice similarly drove widespread K8 expression in glabrous skin of the paws, but in the whisker pads and body skin ectopic K8+ cells were confined to hair follicles and absent from interfollicular regions. Ectopic K8+ cells acquired several characteristics of mature Merkel cells in a time frame similar to that seen during postnatal development of normal Merkel cells. Although ectopic K8+ cell numbers decreased over time, small numbers of these cells remained in deep regions of body skin hair follicles at 3 months post-induction. In adult mice, greater numbers of ectopic K8+ cells were created by Atoh1 induction during anagen versus telogen and following disruption of Notch signaling by conditional deletion of Rbpj in the epidermis. Our data demonstrate that Atoh1 expression is sufficient to produce new Merkel cells in the epidermis, that epidermal cell competency to respond to Atoh1 varies by skin location, developmental age and hair cycle stage, and that the Notch pathway plays a key role in limiting epidermal cell competency to respond to Atoh1 expression.

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“…There is ongoing cellular turnover in touch domes, with constant production of stratified epithelial keratinocytes and cyclical expansion of terminally differentiated Merkel cells that coincides with anagen regeneration in the hair cycle (17). Genetic fate mapping has shown that the progenitors maintaining these two cell types are found among the K17 + cells in the touch dome (18), with unipotent atonal homolog 1 (Atoh1)-positive progenitors maintaining the Merkel cells (19). However, the signaling pathways involved in touch dome and Merkel cell homeostasis remain unclear.…”

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confidence: 99%

Neural Hedgehog signaling maintains stem cell renewal in the sensory touch dome epithelium

Xiao

Thoresen

Williams

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The touch dome is a highly patterned mechanosensory structure in the epidermis composed of specialized keratinocytes in juxtaposition with innervated Merkel cells. The touch dome epithelium is maintained by tissue-specific stem cells, but the signals that regulate the touch dome are not known. We identify touch dome stem cells that are unique among epidermal cells in their activated Hedgehog signaling and ability to maintain the touch dome as a distinct lineage compartment. Skin denervation reveals that renewal of touch dome stem cells requires a perineural microenvironment, and deleting Sonic hedgehog (Shh) in neurons or Smoothened in the epidermis demonstrates that Shh is an essential niche factor that maintains touch dome stem cells. Up-regulation of Hedgehog signaling results in neoplastic expansion of touch dome keratinocytes but no Merkel cell neoplasia. These findings demonstrate that nerve-derived Shh is a critical regulator of lineage-specific stem cells that maintain specialized sensory compartments in the epidermis.

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Unipotent,Atoh1+ progenitors maintain the Merkel cell population in embryonic and adult mice

Abstract: A novel, unipotent progenitor population in the skin characterized by Atoh1 expression gives rise to Merkel cells both during development and adulthood.

Cited by 42 publications

References 49 publications

Touch Receptors Undergo Rapid Remodeling in Healthy Skin

Touch Receptors Undergo Rapid Remodeling in Healthy Skin

EctopicAtoh1expression drives Merkel cell production in embryonic, postnatal and adult epidermis

Neural Hedgehog signaling maintains stem cell renewal in the sensory touch dome epithelium

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