Bmp4 is required for tracheal formation: A novel mouse model for tracheal agenesis

Abstract

Tracheal agenesis/atresia (TA) is a rare but fatal congenital disease in which the breathing tube fails to grow. The etiology of this serious condition remains largely unknown. We found that Bmp signaling is prominently present in the anterior foregut where the tracheal primordium originates and targeted ablation of Bmp4 (Bmp4cko) resulted in a loss-of-trachea phenotype that closely resembles the Floyd type II pathology, the most common form of TA in humans. In Bmp4cko embryos, tracheal specification was not affected, however, its outgrowth was severely impaired due to reduced epithelial and mesenchymal proliferation. In agreement, we also observed significant reduction in the expression of Cyclin D1, a key cell cycle regulator associated with cellular proliferation. However, the proliferative effect of Bmp signaling appears to be independent of Wnt signaling. Interestingly, we found significantly reduced expression of activated extracellular signal-regulated kinase (Erk) in the Bmp4cko ventral foregut, suggesting that Bmp signaling promotes Erk phosphorylation which has been associated with cellular proliferation. This study provides the first evidence linking Bmp signaling to tracheal formation by regulating the proliferative response of the anterior ventral foregut. Our finding sheds light on human tracheal malformations by providing a novel mouse model implicating Bmp signaling, non-canonical Erk activation and cellular proliferation.

Ca v 3.2 T-type calcium channel is required for the NFAT-dependent Sox9 expression in tracheal cartilage

“…The molecular mechanism leading to CTMs is not understood and is believed to be multifactorial. CTMs have been described in mice lacking genes involved in embryonic development [e.g., sonic hedgehog (6), Wnt (83,84), bone morphogenetic protein (85,86), FGFs (87,88)]. Recently, mice with cartilage-specific deletion of Dicer 1 showed abnormal tracheal development because of a lack of ECM deposition (89).…”

Signaling through BMP receptors promotes respiratory identity in the foregut via repression of Sox2

“…Signaling pathways that have been implicated in foregut patterning and/or morphogenesis include sonic hedgehog (SHH) (Litingtung et al, 1998), fibroblast growth factor (FGF) (Que et al, 2007;Serls et al, 2005), WNT (Goss et al, 2009;Harris-Johnson et al, 2009), transforming growth factor  (TGF) (Chen et al, 2007) and bone morphogenetic protein (BMP) pathways (Li et al, 2007;Li et al, 2008;Que et al, 2006). In this study, we focus on the role of BMP signaling in foregut patterning and morphogenesis.…”

“…Bmp4 is expressed in the mesenchyme surrounding the ventral foregut prior to and during emergence of the lung buds (Li et al, 2008;Que et al, 2006;Weaver et al, 1999;Bellusci et al, 1996;Weaver et al, 2003). This expression pattern contrasts with that of BMP antagonist noggin (Nog), which is expressed in the dorsal endoderm (Li et al, 2007;Que et al, 2006).…”

“…Nog mutant mice frequently display esophageal atresia/tracheoesophageal fistula (EA/TEF), which is rescued in a Bmp4 +/- (Que et al, 2006) or Bmp7 -/-genetic background (Li et al, 2007). In addition, conditional inactivation of Bmp4 in the foregut endoderm and surrounding mesenchyme results in tracheal atresia (TA) and lung hypoplasia (Li et al, 2008). Analyses of these Bmp4 mutants led to the conclusion that the primary requirement for BMP signaling is to promote cell proliferation, but not respiratory specification.…”

Developmental Aspects of the Upper Airway: Report from an NHLBI Workshop, March 5-6, 2009

“…Abnormal expression of SHH has been associated with glossoptosis, pyriform aperture stenosis, tracheoesophageal fistula, and/or laryngotracheoesophageal cleft malformations (25). Multiple other cytokines and transcription factors have been implicated in upper airway anomalies (Table 3) (26)(27)(28)(29)(30)(31)(32)(33)(34). It is likely that other mouse models display upper airway abnormalities that have not been identified due to lack of screening by investigators with appropriate knowledge.…”