Mouse models of neutropenia reveal progenitor-stage-specific defects

Nature. 2020 Jun;582(7810):109-114. doi: 10.1038/s41586-020-2227-7. Epub 2020 Apr 22.


Advances in genetics and sequencing have identified a plethora of disease-associated and disease-causing genetic alterations. To determine causality between genetics and disease, accurate models for molecular dissection are required; however, the rapid expansion of transcriptional populations identified through single-cell analyses presents a major challenge for accurate comparisons between mutant and wild-type cells. Here we generate mouse models of human severe congenital neutropenia (SCN) using patient-derived mutations in the GFI1 transcription factor. To determine the effects of SCN mutations, we generated single-cell references for granulopoietic genomic states with linked epitopes1, aligned mutant cells to their wild-type equivalents and identified differentially expressed genes and epigenetic loci. We find that GFI1-target genes are altered sequentially, as cells go through successive states of differentiation. These insights facilitated the genetic rescue of granulocytic specification but not post-commitment defects in innate immune effector function, and underscore the importance of evaluating the effects of mutations and therapy within each relevant cell state.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Candida albicans / immunology
  • Candida albicans / pathogenicity
  • Cell Lineage
  • DNA-Binding Proteins / genetics
  • Disease Models, Animal*
  • Female
  • Granulocyte Precursor Cells / pathology*
  • Humans
  • Immunity, Innate
  • Male
  • Mice
  • Mice, Transgenic
  • Mutation*
  • Neutropenia / congenital
  • Neutropenia / genetics*
  • Neutropenia / immunology
  • Neutropenia / pathology*
  • Neutrophils / immunology
  • Neutrophils / pathology*
  • Transcription Factors / genetics


  • DNA-Binding Proteins
  • GFI1 protein, human
  • Transcription Factors