Elsevier

Developmental Biology

Volume 444, Supplement 1, 1 December 2018, Pages S287-S296
Developmental Biology

Stochastic clonal expansion of “superstars” enhances the reserve capacity of enteric nervous system precursor cells

https://doi.org/10.1016/j.ydbio.2018.01.020Get rights and content
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Highlights

  • Enteric neural crest cells show huge expansion to form the enteric nervous system.

  • Enteric neural crest cells have great ability to regulate their final number.

  • Clonal expansion of enteric neural crest cells is highly unequal.

  • Mathematical models and experiments indicate that huge clones arise stochastically.

  • The enteric nervous system may be influenced by somatic mutations.

Abstract

We quantified cell population increase in the quail embryo enteric nervous system (ENS) from E2.5 (about 1500 cells) to E12 (about 8 million cells). We then probed ENS proliferative capacity by grafting to the chorio-allantoic membrane large (600 cells) and small (40 cells) populations of enteric neural crest (ENC) cells with aneural gut. This demonstrated that ENC cells show an extremely high capacity to regulate their proliferation while forming the ENS. Previous mathematical models and clonal label experiments revealed that a few dominant ENS “superstar” cell clones emerge but most clones are small. The model implied that “superstars” arise stochastically, but the same outcome could arise if “superstars” were pre-determined. We investigated these two modes mathematically and by grafting experiments with large and small numbers of ENCs, each including one EGFP-labelled ENC cell. The stochastic model predicts that the frequency of “superstar” detection increases as the ENC population decreases, the pre-determined model does not. Experimentally, as predicted by the stochastic model, the frequency of “superstar” detection increased with small ENC cell number. We conclude that ENS “superstar” clones achieve this status stochastically. Clonal dominance implies that clonal diversity is greatly reduced and in this case, somatic mutations may affect the phenotype. We suggest that somatic mutations coupled with loss of clonal diversity may contribute to variable penetrance and expressivity in individuals with genetically identical ENS pathologies.

Keywords

Enteric neural crest
Enteric nervous system
Colonisation
Cell proliferation
Mathematical model
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