Limits...
Barx1-mediated inhibition of Wnt signaling in the mouse thoracic foregut controls tracheo-esophageal septation and epithelial differentiation.

Woo J, Miletich I, Kim BM, Sharpe PT, Shivdasani RA - PLoS ONE (2011)

Bottom Line: This expression pattern exactly mirrors the decline in Wnt signaling activity in late development of the adjacent dorsal foregut endoderm and medial mainstem bronchi.The zone of canonical Wnt signaling is abnormally prolonged and expanded in the proximal Barx1(-/-) foregut.Thus, as in the developing stomach, but distinct from the spleen, Barx1 control of thoracic foregut specification and tracheo-esophageal septation is tightly associated with down-regulation of adjacent Wnt pathway activity.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.

ABSTRACT
Mesenchymal cells underlying the definitive endoderm in vertebrate animals play a vital role in digestive and respiratory organogenesis. Although several signaling pathways are implicated in foregut patterning and morphogenesis, and despite the clinical importance of congenital tracheal and esophageal malformations in humans, understanding of molecular mechanisms that allow a single tube to separate correctly into the trachea and esophagus is incomplete. The homoebox gene Barx1 is highly expressed in prospective stomach mesenchyme and required to specify this organ. We observed lower Barx1 expression extending contiguously from the proximal stomach domain, along the dorsal anterior foregut mesenchyme and in mesenchymal cells between the nascent esophagus and trachea. This expression pattern exactly mirrors the decline in Wnt signaling activity in late development of the adjacent dorsal foregut endoderm and medial mainstem bronchi. The hypopharynx in Barx1(-/-) mouse embryos is abnormally elongated and the point of esophago-tracheal separation shows marked caudal displacement, resulting in a common foregut tube that is similar to human congenital tracheo-esophageal fistula and explains neonatal lethality. Moreover, the Barx1(-/-) esophagus displays molecular and cytologic features of respiratory endoderm, phenocopying abnormalities observed in mouse embryos with activated ß-catenin. The zone of canonical Wnt signaling is abnormally prolonged and expanded in the proximal Barx1(-/-) foregut. Thus, as in the developing stomach, but distinct from the spleen, Barx1 control of thoracic foregut specification and tracheo-esophageal septation is tightly associated with down-regulation of adjacent Wnt pathway activity.

Show MeSH

Related in: MedlinePlus

Molecular and histologic evidence for failure of tracheo-esophageal septation in the absence of Barx1.Expression of the respiratory marker NKX2.1 and the stratified epithelial marker p63 in the thoracic foregut of E13.5 Barx1+/+ (A–C) and Barx1−/− (D–F) embryos. The sagittal tissue sections reveal an undivided rostral foregut, with NKX2.1-expressing respiratory epithelial cells (red arrowhead in D) replacing p63-expressing (blue arrow in B and blue arrowhead in E) squamous epithelial cells in the ventral esophageal endoderm. The results are interpreted in diagrams in C, F. (G–I) Histologic and immunologic demonstration of asymmetry in the lining of the distal esophagus in E19.5 Barx1−/− pups, with a stratified squamous epithelium on the dorsal surface and a columnar respiratory epithelium along the ventral surface (arrowheads in G). Immunostaining revealed mutually exclusive NKX2.1 expression in ventral cells (H) and p63 expression in the dorsal epithelium (I). The data represent results from 2 mutant embryos.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3142160&req=5

pone-0022493-g003: Molecular and histologic evidence for failure of tracheo-esophageal septation in the absence of Barx1.Expression of the respiratory marker NKX2.1 and the stratified epithelial marker p63 in the thoracic foregut of E13.5 Barx1+/+ (A–C) and Barx1−/− (D–F) embryos. The sagittal tissue sections reveal an undivided rostral foregut, with NKX2.1-expressing respiratory epithelial cells (red arrowhead in D) replacing p63-expressing (blue arrow in B and blue arrowhead in E) squamous epithelial cells in the ventral esophageal endoderm. The results are interpreted in diagrams in C, F. (G–I) Histologic and immunologic demonstration of asymmetry in the lining of the distal esophagus in E19.5 Barx1−/− pups, with a stratified squamous epithelium on the dorsal surface and a columnar respiratory epithelium along the ventral surface (arrowheads in G). Immunostaining revealed mutually exclusive NKX2.1 expression in ventral cells (H) and p63 expression in the dorsal epithelium (I). The data represent results from 2 mutant embryos.

Mentions: The persistence and sequelae of these defects were apparent in Barx1−/− embryos at E13.5. The common anterior foregut remained thick and elongated, reflecting persistent failure of septation (Fig. 3D–F). The ventral foregut showed high Nkx2.1 and absent p63 expression (arrowheads in Fig. 3D,E), whereas wild-type littermates expressed p63 but not Nkx2.1 in the corresponding region (arrows in Fig. 3A,B). Thus, Nkx2.1-expressing cells extended aberrantly into the ventral esophageal endoderm, a region depleted of p63-expressing cells (Fig. 3D,E). Taken together, these results reveal molecular features of a respiratory endoderm progenitor in the ventral endoderm of the mid-gestation Barx1−/− esophagus. As we reported previously but could not then explain [10], even in late gestation (E19) the ventral surface of the esophagus carries a ciliated, columnar epithelium, distinct from the stratified epithelium of the dorsal surface (arrowheads in Fig. 3G). Immunostaining revealed mutually exclusive NKX2.1 expression in ventral cells and p63 expression in the dorsal epithelium (Fig. 3H,I). These findings indicate that Barx1 is necessary for tracheo-esophageal septation and for proper localization of squamous esophageal and columnar respiratory epithelia originating in the undifferentiated foregut.


Barx1-mediated inhibition of Wnt signaling in the mouse thoracic foregut controls tracheo-esophageal septation and epithelial differentiation.

Woo J, Miletich I, Kim BM, Sharpe PT, Shivdasani RA - PLoS ONE (2011)

Molecular and histologic evidence for failure of tracheo-esophageal septation in the absence of Barx1.Expression of the respiratory marker NKX2.1 and the stratified epithelial marker p63 in the thoracic foregut of E13.5 Barx1+/+ (A–C) and Barx1−/− (D–F) embryos. The sagittal tissue sections reveal an undivided rostral foregut, with NKX2.1-expressing respiratory epithelial cells (red arrowhead in D) replacing p63-expressing (blue arrow in B and blue arrowhead in E) squamous epithelial cells in the ventral esophageal endoderm. The results are interpreted in diagrams in C, F. (G–I) Histologic and immunologic demonstration of asymmetry in the lining of the distal esophagus in E19.5 Barx1−/− pups, with a stratified squamous epithelium on the dorsal surface and a columnar respiratory epithelium along the ventral surface (arrowheads in G). Immunostaining revealed mutually exclusive NKX2.1 expression in ventral cells (H) and p63 expression in the dorsal epithelium (I). The data represent results from 2 mutant embryos.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3142160&req=5

pone-0022493-g003: Molecular and histologic evidence for failure of tracheo-esophageal septation in the absence of Barx1.Expression of the respiratory marker NKX2.1 and the stratified epithelial marker p63 in the thoracic foregut of E13.5 Barx1+/+ (A–C) and Barx1−/− (D–F) embryos. The sagittal tissue sections reveal an undivided rostral foregut, with NKX2.1-expressing respiratory epithelial cells (red arrowhead in D) replacing p63-expressing (blue arrow in B and blue arrowhead in E) squamous epithelial cells in the ventral esophageal endoderm. The results are interpreted in diagrams in C, F. (G–I) Histologic and immunologic demonstration of asymmetry in the lining of the distal esophagus in E19.5 Barx1−/− pups, with a stratified squamous epithelium on the dorsal surface and a columnar respiratory epithelium along the ventral surface (arrowheads in G). Immunostaining revealed mutually exclusive NKX2.1 expression in ventral cells (H) and p63 expression in the dorsal epithelium (I). The data represent results from 2 mutant embryos.
Mentions: The persistence and sequelae of these defects were apparent in Barx1−/− embryos at E13.5. The common anterior foregut remained thick and elongated, reflecting persistent failure of septation (Fig. 3D–F). The ventral foregut showed high Nkx2.1 and absent p63 expression (arrowheads in Fig. 3D,E), whereas wild-type littermates expressed p63 but not Nkx2.1 in the corresponding region (arrows in Fig. 3A,B). Thus, Nkx2.1-expressing cells extended aberrantly into the ventral esophageal endoderm, a region depleted of p63-expressing cells (Fig. 3D,E). Taken together, these results reveal molecular features of a respiratory endoderm progenitor in the ventral endoderm of the mid-gestation Barx1−/− esophagus. As we reported previously but could not then explain [10], even in late gestation (E19) the ventral surface of the esophagus carries a ciliated, columnar epithelium, distinct from the stratified epithelium of the dorsal surface (arrowheads in Fig. 3G). Immunostaining revealed mutually exclusive NKX2.1 expression in ventral cells and p63 expression in the dorsal epithelium (Fig. 3H,I). These findings indicate that Barx1 is necessary for tracheo-esophageal septation and for proper localization of squamous esophageal and columnar respiratory epithelia originating in the undifferentiated foregut.

Bottom Line: This expression pattern exactly mirrors the decline in Wnt signaling activity in late development of the adjacent dorsal foregut endoderm and medial mainstem bronchi.The zone of canonical Wnt signaling is abnormally prolonged and expanded in the proximal Barx1(-/-) foregut.Thus, as in the developing stomach, but distinct from the spleen, Barx1 control of thoracic foregut specification and tracheo-esophageal septation is tightly associated with down-regulation of adjacent Wnt pathway activity.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.

ABSTRACT
Mesenchymal cells underlying the definitive endoderm in vertebrate animals play a vital role in digestive and respiratory organogenesis. Although several signaling pathways are implicated in foregut patterning and morphogenesis, and despite the clinical importance of congenital tracheal and esophageal malformations in humans, understanding of molecular mechanisms that allow a single tube to separate correctly into the trachea and esophagus is incomplete. The homoebox gene Barx1 is highly expressed in prospective stomach mesenchyme and required to specify this organ. We observed lower Barx1 expression extending contiguously from the proximal stomach domain, along the dorsal anterior foregut mesenchyme and in mesenchymal cells between the nascent esophagus and trachea. This expression pattern exactly mirrors the decline in Wnt signaling activity in late development of the adjacent dorsal foregut endoderm and medial mainstem bronchi. The hypopharynx in Barx1(-/-) mouse embryos is abnormally elongated and the point of esophago-tracheal separation shows marked caudal displacement, resulting in a common foregut tube that is similar to human congenital tracheo-esophageal fistula and explains neonatal lethality. Moreover, the Barx1(-/-) esophagus displays molecular and cytologic features of respiratory endoderm, phenocopying abnormalities observed in mouse embryos with activated ß-catenin. The zone of canonical Wnt signaling is abnormally prolonged and expanded in the proximal Barx1(-/-) foregut. Thus, as in the developing stomach, but distinct from the spleen, Barx1 control of thoracic foregut specification and tracheo-esophageal septation is tightly associated with down-regulation of adjacent Wnt pathway activity.

Show MeSH
Related in: MedlinePlus