TY - JOUR
T1 - Transcriptional control of lung alveolar type 1 cell development and maintenance by NK homeobox 2-1
AU - Little, Danielle R.
AU - Gerner-Mauro, Kamryn N.
AU - Flodby, Per
AU - Crandall, Edward D.
AU - Borok, Zea
AU - Akiyama, Haruhiko
AU - Kimura, Shioko
AU - Ostrin, Edwin J.
AU - Chen, Jichao
N1 - Funding Information:
We thank Kenneth Dunner Jr. for help with SEM and TEM. We would also like to thank Dr. Richard Behringer for his suggestions. This work was supported by the University of Texas MD Anderson Cancer Center institutional research grant and start-up funds, NIH R01HL130129 (J.C.), F31HL139095 (D.R.L.), and R35HL135747 (Z.B.), and Cancer Center Support Grant CA 16672.
Funding Information:
ACKNOWLEDGMENTS. We thank Kenneth Dunner Jr. for help with SEM and TEM. We would also like to thank Dr. Richard Behringer for his suggestions. This work was supported by the University of Texas MD Anderson Cancer Center institutional research grant and start-up funds, NIH R01HL130129 (J.C.), F31HL139095 (D.R.L.), and R35HL135747 (Z.B.), and Cancer Center Support Grant CA 16672.
Publisher Copyright:
© 2019 National Academy of Sciences. All rights reserved.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
KW - Alveolar type 1 cell
KW - Alveologenesis
KW - Lung development
KW - NK homeobox 2-1
KW - Transcriptional control
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U2 - 10.1073/pnas.1906663116
DO - 10.1073/pnas.1906663116
M3 - Article
C2 - 31548395
AN - SCOPUS:85073076735
SN - 0027-8424
VL - 116
SP - 20545
EP - 20555
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 41
ER -