Robust hematopoietic progenitor cell commitment in the presence of a conflicting cue

Najaf A. Shah, Marshall J. Levesque, Arjun Raj, Casim A. Sarkar

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Hematopoietic lineage commitment is regulated by cytokines and master transcription factors, but it remains unclear how a progenitor cell chooses a lineage in the face of conflicting cues. Through transcript counting in megakaryocyte-erythroid progenitors undergoing erythropoiesis, we show that the expression levels of the pro-erythropoiesis transcription factor EKLF (also known as KLF1) and receptor EpoR are inversely correlated with their pro-megakaryopoiesis counterparts, FLI-1 and TpoR (also known as MPL). Notably, as progenitors commit to the erythrocyte lineage, EpoR is upregulated and TpoR is strongly downregulated, thus boosting the potency of the pro-erythropoiesis cue erythropoietin and effectively eliminating the activity of the pro-megakaryopoiesis cue thrombopoietin. Based on these findings, we propose a newmodel for exclusive decision making that explicitly incorporates signals from extrinsic cues, and we experimentally confirm a model prediction of temporal changes in transcript noise levels in committing progenitors. Our study suggests that lineage-specific receptor levels can modulate potencies of cues to achieve robust commitment decisions.

Original languageEnglish (US)
Pages (from-to)3009-3017
Number of pages9
JournalJournal of cell science
Volume128
Issue number15
DOIs
StatePublished - 2015

Keywords

  • Conflicting cue
  • Hematopoiesis
  • Lineage commitment

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