<i>T‐box</i> gene products are required for mesenchymal induction of epithelial branching in the embryonic mouse lung

Cebra‐Thomas, Judith A.; Bromer, Jason G.; Gardner, R J Van Beneden L D Rhodes G R; Lam, Gordon K.; Sheipe, Hillary; Gilbert, Scott F.

doi:10.1002/dvdy.10208

Cited by 65 publications

(57 citation statements)

References 74 publications

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“…Previous work reported the expression of Tbx2 and Tbx3 in the mesenchymal compartment of the developing lung, but a functional significance has not been assigned to this expression [19,20]. Here, we show by loss-and gain-of-function experiments in the mouse that Tbx2 is required and sufficient to maintain proliferation and inhibit differentiation in the mesenchymal compartment of the developing lung.…”

Section: Introductionmentioning

confidence: 53%

“…An antisense oligonucleotide approach with cultured lung rudiments and more recently conditional gene targeting demonstrated a requirement for mesenchymal Tbx4 and Tbx5 in the regulation of pulmonary branching morphogenesis [19,33]. Tbx4 and Tbx5 genetically interact with Fgf10 during lung growth and branching, and may direct transcriptional activation of Fgf10 that encodes a potent growth factor in the lung but also in other developmental contexts [33,34].…”

Section: Coexpression Of T-box Genes In the Developing Lung Mesenchymementioning

confidence: 99%

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Tbx2 Controls Lung Growth by Direct Repression of the Cell Cycle Inhibitor Genes Cdkn1a and Cdkn1b

Lüdtke¹,

Farin²,

Rudat³

et al. 2014

Pneumologie

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Vertebrate organ development relies on the precise spatiotemporal orchestration of proliferation rates and differentiation patterns in adjacent tissue compartments. The underlying integration of patterning and cell cycle control during organogenesis is insufficiently understood. Here, we have investigated the function of the patterning T-box transcription factor gene Tbx2 in lung development. We show that lungs of Tbx2-deficient mice are markedly hypoplastic and exhibit reduced branching morphogenesis. Mesenchymal proliferation was severely decreased, while mesenchymal differentiation into fibrocytes was prematurely induced. In the epithelial compartment, proliferation was reduced and differentiation of alveolar epithelial cells type 1 was compromised. Prior to the observed cellular changes, canonical Wnt signaling was downregulated, and Cdkn1a (p21) and Cdkn1b (p27) (two members of the Cip/Kip family of cell cycle inhibitors) were strongly induced in the Tbx2-deficient lung mesenchyme. Deletion of both Cdkn1a and Cdkn1b rescued, to a large degree, the growth deficits of Tbx2-deficient lungs. Prolongation of Tbx2 expression into adulthood led to hyperproliferation and maintenance of mesenchymal progenitor cells, with branching morphogenesis remaining unaffected. Expression of Cdkn1a and Cdkn1b was ablated from the lung mesenchyme in this gain-of-function setting. We further show by ChIP experiments that Tbx2 directly binds to Cdkn1a and Cdkn1b loci in vivo, defining these two genes as direct targets of Tbx2 repressive activity in the lung mesenchyme. We conclude that Tbx2-mediated regulation of Cdkn1a and Cdkn1b represents a crucial node in the network integrating patterning information and cell cycle regulation that underlies growth, differentiation, and branching morphogenesis of this organ.

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Section: Introductionmentioning

confidence: 53%

Section: Coexpression Of T-box Genes In the Developing Lung Mesenchymementioning

confidence: 99%

Tbx2 Controls Lung Growth by Direct Repression of the Cell Cycle Inhibitor Genes Cdkn1a and Cdkn1b

Lüdtke¹,

Farin²,

Rudat³

et al. 2014

Pneumologie

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“…On the other hand, several conserved binding sites for lung-related transcription factors were detected, including binding sites for Smad4, Nkx2.5, Tbx5 and Isl1. Tbx5 is thought to directly control Fgf10 expression in the lung mesenchyme [25]. Moreover, a recent report has shown that ISL1 regulates FGF10 transcription within the second heart field by binding to an enhancer element in intron 1 of FGF10 Figure 6.…”

Section: Discussionmentioning

confidence: 99%

Characterization of a novel Fibroblast growth factor 10 (Fgf10) knock-in mouse line to target mesenchymal progenitors during embryonic development

Agha¹,

Alam²,

Carraro³

et al. 2012

Pneumologie

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Fibroblast growth factor 10 (Fgf10) is a key regulator of diverse organogenetic programs during mouse development, particularly branching morphogenesis. Fgf10-null mice suffer from lung and limb agenesis as well as cecal and colonic atresia and are thus not viable. To date, the Mlcv1v-nLacZ-24 transgenic mouse strain (referred to as Fgf10 LacZ ), which carries a LacZ insertion 114 kb upstream of exon 1 of Fgf10 gene, has been the only strain to allow transient lineage tracing of Fgf10-positive cells. Here, we describe a novel Fgf10 Cre-ERT2 knock-in line (Fgf10 iCre ) in which a Cre-ERT2-IRES-YFP cassette has been introduced in frame with the ATG of exon 1 of Fgf10 gene. Our studies show that Cre-ERT2 insertion disrupts Fgf10 function. However, administration of tamoxifen to Fgf10 iCre ; Tomato flox double transgenic embryos or adult mice results in specific labeling of Fgf10-positive cells, which can be lineage-traced temporally and spatially. Moreover, we show that the Fgf10 iCre line can be used for conditional gene inactivation in an inducible fashion during early developmental stages. We also provide evidence that transcription factors located in the first intron of Fgf10 gene are critical for maintaining Fgf10 expression over time. Thus, the Fgf10 iCre line should serve as a powerful tool to explore the functions of Fgf10 in a controlled and stage-specific manner.

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“…In contrast to dominant interactions between ntl and fgf8, we could not find evidence that reduction of spt function could dominantly enhance the phenotype of fgf8 mutant embryos, suggesting that the interactions between fgf8 and ntl are stronger than those between fgf8 and spt. Genetic interactions between the Fgf signaling pathway and T-box transcription factors is becoming a common theme in vertebrate development, as similar interactions have been proposed to play key roles in development of limbs (Ng et al, 2002) the cardiovascular system (Vitelli et al, 2002) and lungs (Cebra-Thomas et al, 2003).…”

Section: Fgf8 and Fgf24 Are Components Of The Fgf Signaling Pathway Tmentioning

confidence: 95%

Zebrafish fgf24functions withfgf8to promote posterior mesodermal development

2003

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Fibroblast growth factor (Fgf) signaling plays an important role during development of posterior mesoderm in vertebrate embryos. Blocking Fgf signaling by expressing a dominant-negative Fgf receptor inhibits posterior mesoderm development. In mice, Fgf8 appears to be the principal ligand required for mesodermal development, as mouse Fgf8 mutants do not form mesoderm. In zebrafish, Fgf8 is encoded by the acerebellarlocus, and, similar to its mouse otholog, is expressed in early mesodermal precursors during gastrulation. However, zebrafish fgf8 mutants have only mild defects in posterior mesodermal development, suggesting that it is not the only Fgf ligand involved in the development of this tissue. We report here the identification of an fgf8-related gene in zebrafish, fgf24, that is co-expressed with fgf8 in mesodermal precursors during gastrulation. Using morpholino-based gene inactivation, we have analyzed the function of fgf24 during development. We found that inhibiting fgf24 function alone has no affect on the formation of posterior mesoderm. Conversely, inhibiting fgf24 function in embryos mutant for fgf8 blocks the formation of most posterior mesoderm. Thus, fgf8 and fgf24 are together required to promote posterior mesodermal development. We provide both phenotypic and genetic evidence that these Fgf signaling components interact with no tailand spadetail, two zebrafish T-box transcription factors that are required for the development of all posterior mesoderm. Last, we show that fgf24 is expressed in early fin bud mesenchyme and that inhibiting fgf24 function results in viable fish that lack pectoral fins.

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T‐box gene products are required for mesenchymal induction of epithelial branching in the embryonic mouse lung

Cited by 65 publications

References 74 publications

Tbx2 Controls Lung Growth by Direct Repression of the Cell Cycle Inhibitor Genes Cdkn1a and Cdkn1b

Tbx2 Controls Lung Growth by Direct Repression of the Cell Cycle Inhibitor Genes Cdkn1a and Cdkn1b

Characterization of a novel Fibroblast growth factor 10 (Fgf10) knock-in mouse line to target mesenchymal progenitors during embryonic development

Zebrafish fgf24functions withfgf8to promote posterior mesodermal development

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