The absence of SOX2 in the anterior foregut alters the esophagus into trachea and bronchi in both epithelial and mesenchymal components

Abstract

In the anterior foregut (AFG) of mouse embryos, the transcription factor SOX2 is expressed in the epithelia of the esophagus and proximal branches of respiratory organs comprising the trachea and bronchi, whereas NKX2.1 is expressed only in the epithelia of respiratory organs. Previous studies using hypomorphic Sox2 alleles have indicated that reduced SOX2 expression causes the esophageal epithelium to display some respiratory organ characteristics. In the present study, we produced mouse embryos with AFG-specific SOX2 deficiency. In the absence of SOX2 expression, a single NKX2.1expressing epithelial tube connected the pharynx and the stomach, and a pair of bronchi developed in the middle of the tube. Expression patterns of NKX2.1 and SOX9 revealed that the anterior and posterior halves of SOX2-deficient AFG epithelial tubes assumed the characteristics of the trachea and bronchus, respectively. In addition, we found that mesenchymal tissues surrounding the SOX2-deficient NKX2.1-expressing epithelial tube changed to those surrounding the trachea and bronchi in the anterior and posterior halves, as indicated by the arrangement of smooth muscle cells and SOX9expressing cells and by the expression of Wnt4 (esophagus specific), Tbx4 (respiratory organ specific), and Hoxb6 (distal bronchus specific). The impact of mesenchyme-derived signaling on the early stage of AFG epithelial specification has been indicated. Our study demonstrated an opposite trend where epithelial tissue specification causes concordant changes in mesenchymal tissues, indicating a reciprocity of epithelial-mesenchymal interactions.

Disruption of a Hedgehog-Foxf1-Rspo2 signaling axis leads to tracheomalacia and a loss of Sox9+ tracheal chondrocytes

“…Nkx2-1 and Sox2 are transcription factors required for the development of the tracheal and esophageal endoderm epithelia, respectively ( Minoo et al, 1999 ; Que et al, 2007 ). Nkx2-1 −/− mutants have a single undivided foregut tube of esophageal character, whereas deletion of Sox2 from the foregut results in an undivided foregut tube of tracheal character ( Kuwahara et al, 2020 ; Que et al, 2009 , 2007 ; Teramoto et al, 2020 ; Trisno et al, 2018 ). A re-analysis of these mutants showed that the single undivided foregut in both the Sox2 and Nkx2-1 mutant embryos was correctly patterned.…”

Molecular crosstalk in tracheal development and its recurrence in adult tissue regeneration

“…The complementary distribution of Nkx2.1 and Sox2 determines the DV pattern of the foregut tube. [37][38][39] Nkx2.1, an essential TF for trachea and lung specification, 40 is initially expressed by E9.0, 24 specifically in the ventral area of the anterior foregut endoderm. In Nkx2.1 null mice, the trachea fails to appear, resulting in tracheal agenesis, 38 although bilateral bronchial tubes arise from the esophagus and connect to profoundly hypoplastic lungs.…”

“…The complementary distribution of Nkx2.1 and Sox2 determines the DV pattern of the foregut tube. 37 , 38 , 39 …”

Disruption of a Hedgehog-Foxf1-Rspo2 Signaling Axis Leads to Tracheomalacia and a Loss of Sox9+ Tracheal Chondrocytes

“…Nkx2-1 and Sox2 are transcription factors required for development of the tracheal and esophageal endoderm epithelial, respectively (Minoo et al, 1999;Que et al, 2007). Nkx2-1 -/mutants have a single undivided foregut tube of esophageal character, whereas deletion of Sox2 from the foregut results in an undivided foregut tube of respiratory character (Kuwahara et al, 2020;Que et al, 2009;Que et al, 2007;Teramoto et al, 2020;Trisno et al, 2018). A reanalysis of these mutants showed that both the Sox2 and Nkx2-1-null embryos exhibited a downregulation of Foxf1 and upregulation of Sox9 in the ventral mesenchyme, although there were far fewer Sox9+ chondrocytes in the Nkx2-1 mutant compared to the Sox2 mutant or wildtype controls (Supplemental Figure 2A) (Que et al, 2009;Teramoto et al, 2020).…”

“…Nkx2-1 -/mutants have a single undivided foregut tube of esophageal character, whereas deletion of Sox2 from the foregut results in an undivided foregut tube of respiratory character (Kuwahara et al, 2020;Que et al, 2009;Que et al, 2007;Teramoto et al, 2020;Trisno et al, 2018). A reanalysis of these mutants showed that both the Sox2 and Nkx2-1-null embryos exhibited a downregulation of Foxf1 and upregulation of Sox9 in the ventral mesenchyme, although there were far fewer Sox9+ chondrocytes in the Nkx2-1 mutant compared to the Sox2 mutant or wildtype controls (Supplemental Figure 2A) (Que et al, 2009;Teramoto et al, 2020). Together, these data indicate that the emergence of tracheal chondrocytes with an upregulation of Sox9 and a downregulation of Foxf1 is influenced by the epithelial identity, but not dependent on tracheoesophageal separation.…”