Genome‐scale study of transcription factor expression in the branching mouse lung

Herriges, John; Yi, Lan; Hines, Elizabeth A.; Harvey, Julie F.; Xu, Guoliang; Gray, Paul A.; Ma, Qiufu; Sun, Xin

doi:10.1002/dvdy.23823

Cited by 42 publications

(38 citation statements)

References 242 publications

(271 reference statements)

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“…Sox9 is expressed in the distal progenitor population, which gives rise to all cell types of the lung, and Sox9 expression is down-regulated concomitant with onset of cytodifferentiation in the distal epithelium (13)(14)(15)(16)(17). In addition, we observed a significant decrease in Id2 mRNA expression in Sox9 LOF lungs at E14.5 by qRT-PCR (SI Appendix, Fig.…”

Section: Epithelial-specific Loss and Gain Of Sox9 Causes Severe Branmentioning

confidence: 71%

“…Because this distal epithelium is a highly proliferative population of cells, a fine balance between proliferation and differentiation must be maintained during lung development (14). Several transcription factors are expressed specifically in the distal branching epithelium including Nmyc, Id2, and Sox9 (13)(14)(15)(16)(17). Nmyc plays an important role in maintaining the progenitor population in an undifferentiated state and in driving proliferation (14).…”

mentioning

confidence: 99%

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Sox9 plays multiple roles in the lung epithelium during branching morphogenesis

Rockich¹,

Hrycaj

Shih

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

250

261

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Lung branching morphogenesis is a highly orchestrated process that gives rise to the complex network of gas-exchanging units in the adult lung. Intricate regulation of signaling pathways, transcription factors, and epithelial-mesenchymal cross-talk are critical to ensuring branching morphogenesis occurs properly. Here, we describe a role for the transcription factor Sox9 during lung branching morphogenesis. Sox9 is expressed at the distal tips of the branching epithelium in a highly dynamic manner as branching occurs and is down-regulated starting at embryonic day 16.5, concurrent with the onset of terminal differentiation of type 1 and type 2 alveolar cells. Using epithelial-specific genetic loss-and gain-of-function approaches, our results demonstrate that Sox9 controls multiple aspects of lung branching. Fine regulation of Sox9 levels is required to balance proliferation and differentiation of epithelial tip progenitor cells, and loss of Sox9 leads to direct and indirect cellular defects including extracellular matrix defects, cytoskeletal disorganization, and aberrant epithelial movement. Our evidence shows that unlike other endoderm-derived epithelial tissues, such as the intestine, Wnt/β-catenin signaling does not regulate Sox9 expression in the lung. We conclude that Sox9 collectively promotes proper branching morphogenesis by controlling the balance between proliferation and differentiation and regulating the extracellular matrix.organogenesis | campomelic dysplasia

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Section: Epithelial-specific Loss and Gain Of Sox9 Causes Severe Branmentioning

confidence: 71%

mentioning

confidence: 99%

Sox9 plays multiple roles in the lung epithelium during branching morphogenesis

Rockich¹,

Hrycaj

Shih

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

250

261

View full text Add to dashboard Cite

show abstract

“…The day 28 GFP -population was enriched for diverse but predominantly liver (APOA2, FGB, AFP, CDH17, and TF) and intestinal (CDX2, CDH17, and GIF) markers (Supplemental Table 2). In addition to HNF1B, HOXA1, and FOXA1 ( Figure 4D) (26)(27)(28), suggesting a constellation of transcripts better able to distinguish these 2 iPSCderived populations.…”

Section: Tp63mentioning

confidence: 99%

Prospective isolation of NKX2-1–expressing human lung progenitors derived from pluripotent stem cells

Hawkins¹,

Krämer²,

Jacob³

et al. 2017

Journal of Clinical Investigation

192

308

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“…The PEA3 subgroup of the ETS family of transcription factors, comprised of ETS transcription variants 1, 4, and 5 (Etv1, Etv4, and Etv5) (8), is known to be engaged by Ras/MAPK signaling. Etv4 and Etv5 are expressed in distal lung epithelium during development and are involved in branching morphogenesis and epithelial cell differentiation (9)(10)(11). Alveolar epithelial cells in the adult lung also express Etv5 (7,12), but a critical role for Etv5 in this setting remains elusive.…”

mentioning

confidence: 99%

Transcription factor Etv5 is essential for the maintenance of alveolar type II cells

Zhang¹,

Newton²,

Kummerfeld³

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

112

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Alveolar type II (AT2) cell dysfunction contributes to a number of significant human pathologies including respiratory distress syndrome, lung adenocarcinoma, and debilitating fibrotic diseases, but the critical transcription factors that maintain AT2 cell identity are unknown. Here we show that the E26 transformation-specific (ETS) family transcription factor Etv5 is essential to maintain AT2 cell identity. Deletion of Etv5 from AT2 cells produced gene and protein signatures characteristic of differentiated alveolar type I (AT1) cells. Consistent with a defect in the AT2 stem cell population, Etv5 deficiency markedly reduced recovery following bleomycin-induced lung injury. Lung tumorigenesis driven by mutant KrasG12D was also compromised by Etv5 deficiency. ERK activation downstream of Ras was found to stabilize Etv5 through inactivation of the cullin-RING ubiquitin ligase CRL4 COP1/DET1 that targets Etv5 for proteasomal degradation. These findings identify Etv5 as a critical output of Ras signaling in AT2 cells, contributing to both lung homeostasis and tumor initiation.A lveolar type II (AT2) cells are a stem cell population that self renews and differentiates into alveolar type I (AT1) cells during lung homeostasis or in response to injury (1, 2). They also give rise to lung adenocarcinoma induced by oncogenic Kras (1, 3-5). AT2 cells are derived from bipotent progenitor cells at the sacculation stage (1). In the adult lung, mature AT2 cells also secrete surfactant phospholipids to maintain normal alveolar function. Sustained Kras activity stimulates the self-renewal of AT2 cells, which eventually leads to abnormal tissue growth (1). An AT2 gene-expression signature has been reported (6, 7), but it is unclear how the identity of AT2 cells is specified and maintained.Given that Ras/MAPK signaling is essential for the self-renewal of AT2 cells and for the initiation of lung adenocarcinoma, identification of the transcription factors that are activated by Ras in AT2 cells is a step toward defining the transcriptional programs underlying AT2 stemness. The PEA3 subgroup of the ETS family of transcription factors, comprised of ETS transcription variants 1, 4, and 5 (Etv1, Etv4, and Etv5) (8), is known to be engaged by Ras/MAPK signaling. Etv4 and Etv5 are expressed in distal lung epithelium during development and are involved in branching morphogenesis and epithelial cell differentiation (9-11). Alveolar epithelial cells in the adult lung also express Etv5 (7, 12), but a critical role for Etv5 in this setting remains elusive.PEA3 transcription factors are also implicated in tumorigenesis. Overexpression of ETV1 or ETV4 has been linked to prostate cancer (13,14), and stabilization of ETV1 by mutant, active tyrosine kinase receptor KIT is thought to drive an oncogenic program in gastrointestinal stromal tumors (GIST) (15). ETV1, ETV4, and ETV5 are labile proteins because of their regulation by the ubiquitin-proteasome system. In GIST, ETV1 protein is stabilized by activation of the Ras/MAPK pathway through an unkno...

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Genome‐scale study of transcription factor expression in the branching mouse lung

Cited by 42 publications

References 242 publications

Sox9 plays multiple roles in the lung epithelium during branching morphogenesis

Sox9 plays multiple roles in the lung epithelium during branching morphogenesis

Prospective isolation of NKX2-1–expressing human lung progenitors derived from pluripotent stem cells

Transcription factor Etv5 is essential for the maintenance of alveolar type II cells

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