Wnt-responsive element controls Lef-1 promoter expression during submucosal gland morphogenesis

Driskell, Ryan R.; Liu, Xiaoming; Luo, Meihui; Filali, Mohammed; Zhou, Weihong; Abbott, Duane; Cheng, Ningli; Moothart, Chris; Engelhardt, John F.

doi:10.1152/ajplung.00026.2004

Cited by 35 publications

(52 citation statements)

References 35 publications

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“…The shorter Lef-1 isoform is produced from a second (P2) promoter located in the second intron of the LEF-1 locus (27,30,34). Recent studies have shown that the LEF-1 promoter is transcriptionally responsive to Wnt/Tcf/␤-catenin induction (12,18,34). PITX2 and Lef-1 interact independently of ␤-catenin.…”

Section: Discussionmentioning

confidence: 99%

PITX2 and β-Catenin Interactions Regulate Lef-1 Isoform Expression

Amen

Liu

Vadlamudi

et al. 2007

Molecular and Cellular Biology

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105

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Lef-1 and PITX2 function in the Wnt signaling pathway by recruiting and interacting with ␤-catenin to activate target genes. Chromatin immunoprecipitation (ChIP) assays identified the Lef-1 promoter as a PITX2 downstream target. Transgenic mice expressing LacZ driven by the 2.5-kb LEF-1 promoter demonstrated expression in the tooth epithelium correlated with endogenous Lef-1 FL epithelial expression. PITX2 isoforms regulate the LEF-1 promoter, and ␤-catenin synergistically enhanced activation of the LEF-1 promoter in combination with PITX2 and Lef-1 isoforms. PITX2 enhances endogenous expression of the full-length ␤-catenin-dependent Lef-1 isoform (Lef-1 FL) while decreasing expression of the N-terminally truncated ␤-catenin-independent isoform. Our research revealed a novel interaction between PITX2, Lef-1, and ␤-catenin in which the Lef-1 ␤-catenin binding domain is dispensable for its interaction with PITX2. PITX2 interacts with two sites within the Lef-1 protein. Furthermore, ␤-catenin interacts with the PITX2 homeodomain and Lef-1 interacts with the PITX2 C-terminal tail. Lef-1 and ␤-catenin interact simultaneously and independently with PITX2 through two different sites to regulate PITX2 transcriptional activity. These data support a role for PITX2 in cell proliferation, migration, and cell division through differential Lef-1 isoform expression and interactions with Lef-1 and ␤-catenin.Pitx2 and Lef-1 encode two transcription factors whose expression can be regulated by early signaling events involved in numerous developmental programs. Pitx2 and Lef-1 are differentially expressed in many tissues, and they demonstrate overlapping expression during tooth development. Lef-1 can be activated by BMP, Wnt, Smads, and transforming growth factor ␤ signaling (18,32,33). Furthermore, Lef-1 transcriptional activity is regulated by its interaction with ␤-catenin. Secreted

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Section: Discussionmentioning

confidence: 99%

PITX2 and β-Catenin Interactions Regulate Lef-1 Isoform Expression

Amen

Liu

Vadlamudi

et al. 2007

Molecular and Cellular Biology

Self Cite

105

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“…To date, a number of signaling pathways (including those involving wingless 1 int-1 [Wnt], bone morphogenetic protein [BMP], fibroblast growth factor [FGF] Notch, and Hedgehog) and their downstream effectors or modulators have been identified as important mediators of cell-fate specification during the morphogenesis of glandular organs. For example, the HMG-box transcriptional factor lymphoid enhancer binding factor (Lef-1) of the Wnt pathway is involved in the initiation of the development of SMGs and a wide range of other epithelial, bud-forming organs, including mammary glands, teeth, and hair follicles (37)(38)(39)(40)(41). Like Lef-1, other transcription factors, such as Pax6 and Msx1/2, have been shown to be involved in bud formation of glandular organs (42,43).…”

Section: Molecular Mechanisms That Specify Formation Of the Smg Stem mentioning

confidence: 99%

“…Mice lacking the Lef-1 gene are impaired in bud formation of the mammary gland, tooth, vibrissa, hair, and airway/nasal SMGs, suggesting that Lef-1 expression is required for formation of these organs (38)(39)(40)(41). In the context of airway SMG development, expression of Lef-1 at both the mRNA and protein levels is highly induced during the early bud stage, in which three to five cells aggregate within the surface epithelium before invagination (37)(38)(39)(40). During later stages of gland development, Lef-1 expression is restricted to the cells in the most distal invading tips of the tubules.…”

Section: Molecular Mechanisms That Specify Formation Of the Smg Stem mentioning

confidence: 99%

“…Furthermore, chromatin immunoprecipitation (ChIP) assays have suggested that TCF4 can bind the WRE in airway epithelial cells (40) and other cell types (66). The analysis of mice expressing bgalactosidase or EGFP reporter transgenes under the control of the 2.5-kb Lef-1 promoter fragment has indicated that this promoter segment alone is sufficient to regulate expression in tracheal and nasal SMG buds (39,40). Furthermore, in this model system, the deletion of the 110-bp WRE from the Lef-1 promoter led to a lack of expression in gland buds (39).…”

Section: Molecular Mechanisms That Specify Formation Of the Smg Stem mentioning

confidence: 99%

“…The analysis of mice expressing bgalactosidase or EGFP reporter transgenes under the control of the 2.5-kb Lef-1 promoter fragment has indicated that this promoter segment alone is sufficient to regulate expression in tracheal and nasal SMG buds (39,40). Furthermore, in this model system, the deletion of the 110-bp WRE from the Lef-1 promoter led to a lack of expression in gland buds (39). Interestingly, the expression of endogenous Lef-1 and a Lef-1 promoter-driven reporter gene was significantly reduced or absent in SMG buds of Wnt3A-deficient mice (40).…”

Section: Molecular Mechanisms That Specify Formation Of the Smg Stem mentioning

confidence: 99%

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The Glandular Stem/Progenitor Cell Niche in Airway Development and Repair

Liu¹,

Engelhardt²

2008

Proceedings of the American Thoracic Society

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Airway submucosal glands (SMGs) are major secretory structures that lie beneath the epithelium of the cartilaginous airway. These glands are believed to play important roles in normal lung function and airway innate immunity by secreting antibacterial factors, mucus, and fluid into the airway lumen. Recent studies have suggested that SMGs may additionally serve as a protective niche for adult epithelial stem/progenitor cells of the proximal airways. As in the case of other adult stem cell niches, SMGs are believed to provide the localized environmental signals required to both maintain and mobilize stem/progenitor cells, in the setting of normal cellular turnover or injury. Aberrant proliferation and differentiation of glandular stem/progenitor cells may be associated with several hypersecretory lung diseases, including chronic bronchitis, asthma, and cystic fibrosis. To better understand the molecular mechanisms that regulate the specification and proliferation of glandular stem/ progenitor cells in lung diseases associated with SMG hypertrophy and hyperplasia, researchers have begun to search for the molecular signals and cell types responsible for establishing the glandular stem/progenitor cell niche, and to dissect how these determinants of the niche change in the setting of proximal airway injury and repair. Such studies have revealed certain similarities between stem/ progenitor cell niches of the distal conducting airways and the SMGs of the proximal airways.

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Intercellular growth factor signaling and the development of mouse tracheal submucosal glands

Rawlins

Hogan

2005

Developmental Dynamics

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To provide a genetic framework for investigating changes in airway submucosal gland function in human respiratory disease, we have investigated their counterparts in normal and mutant mice. We describe their morphogenesis in relation to the expression of genes encoding conserved intercellular signaling pathways. Submucosal glands are severely reduced in number and size in mice heterozygous for Fgf10. Glands are completely absent in mice lacking Ectodysplasin (Eda) and Edaradd (Eda receptor adaptor protein), members of the tumor necrosis (TNF) superfamily of signaling factors. Furthermore, components of the Eda and closely related pathways are transcribed throughout the respiratory system in the adult mouse. Finally, the temporal and spatial pattern of Bmp4 expression suggests that it may control submucosal gland development and homeostasis. Taken together, our observations have important implications for the better understanding of the submucosal gland remodeling that occurs in human respiratory disease.

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Wnt-responsive element controls Lef-1 promoter expression during submucosal gland morphogenesis

Cited by 35 publications

References 35 publications

PITX2 and β-Catenin Interactions Regulate Lef-1 Isoform Expression

PITX2 and β-Catenin Interactions Regulate Lef-1 Isoform Expression

The Glandular Stem/Progenitor Cell Niche in Airway Development and Repair

Intercellular growth factor signaling and the development of mouse tracheal submucosal glands

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