Transcriptional control of lung alveolar type 1 cell development and maintenance by NK homeobox 2-1

Danielle R. Little, Kamryn N. Gerner-Mauro, Per Flodby, Edward D. Crandall, Zea Borok, Haruhiko Akiyama, Shioko Kimura, Edwin J. Ostrin, Jichao Chen

Research output: Contribution to journalArticle

Abstract

The extraordinarily thin alveolar type 1 (AT1) cell constitutes nearly the entire gas exchange surface and allows passive diffusion of oxygen into the blood stream. Despite such an essential role, the transcriptional network controlling AT1 cells remains unclear. Using cell-specific knockout mouse models, genomic profiling, and 3D imaging, we found that NK homeobox 2-1 (Nkx2-1) is expressed in AT1 cells and is required for the development and maintenance of AT1 cells. Without Nkx2-1, developing AT1 cells lose 3 defining features—molecular markers, expansive morphology, and cellular quiescence—leading to alveolar simplification and lethality. NKX2-1 is also cell-autonomously required for the same 3 defining features in mature AT1 cells. Intriguingly, Nkx2-1 mutant AT1 cells activate gastrointestinal (GI) genes and form dense microvilli-like structures apically. Single-cell RNA-seq supports a linear transformation of Nkx2-1 mutant AT1 cells toward a GI fate. Whole lung ChIP-seq shows NKX2-1 binding to 68% of genes that are down-regulated upon Nkx2-1 deletion, including 93% of known AT1 genes, but near-background binding to up-regulated genes. Our results place NKX2-1 at the top of the AT1 cell transcriptional hierarchy and demonstrate remarkable plasticity of an otherwise terminally differentiated cell type.

Original languageEnglish (US)
Pages (from-to)20545-20555
Number of pages11
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number41
DOIs
StatePublished - Jan 1 2019

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Alveolar Epithelial Cells
Homeobox Genes
Maintenance
Lung
Genes
NK 2
Gene Regulatory Networks
Microvilli
Knockout Mice
Gases
RNA
Oxygen

Keywords

  • Alveolar type 1 cell
  • Alveologenesis
  • Lung development
  • NK homeobox 2-1
  • Transcriptional control

ASJC Scopus subject areas

  • General

Cite this

Transcriptional control of lung alveolar type 1 cell development and maintenance by NK homeobox 2-1. / Little, Danielle R.; Gerner-Mauro, Kamryn N.; Flodby, Per; Crandall, Edward D.; Borok, Zea; Akiyama, Haruhiko; Kimura, Shioko; Ostrin, Edwin J.; Chen, Jichao.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, No. 41, 01.01.2019, p. 20545-20555.

Research output: Contribution to journalArticle

Little, Danielle R. ; Gerner-Mauro, Kamryn N. ; Flodby, Per ; Crandall, Edward D. ; Borok, Zea ; Akiyama, Haruhiko ; Kimura, Shioko ; Ostrin, Edwin J. ; Chen, Jichao. / Transcriptional control of lung alveolar type 1 cell development and maintenance by NK homeobox 2-1. In: Proceedings of the National Academy of Sciences of the United States of America. 2019 ; Vol. 116, No. 41. pp. 20545-20555.
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