Wnt ligands signal in a cooperative manner to promote foregut organogenesis

Abstract

Endoderm-mesenchyme cross-talk is a central process in the development of foregut-derived organs. How signaling pathways integrate the activity of multiple ligands to guide organ development is poorly understood. We show that two Wnt ligands, Wnt2 and Wnt7b, cooperatively induce Wnt signaling without affecting the stabilization of the Wnt canonical effector β-catenin despite it being necessary for Wnt2-Wnt7b cooperativity. Wnt2-Wnt7b cooperation is specific for mesenchymal cell lineages and the combined loss of Wnt2 and Wnt7b leads to more severe developmental defects in the lung than loss of Wnt2 or Wnt7b alone. Highthroughput small-molecule screens and biochemical assays reveal that the Pdgf pathway is required for cooperative Wnt2-Wnt7b signaling. Inhibition of Pdgf signaling in cell culture reduces Wnt2-Wnt7b cooperative signaling. Moreover, inhibition of Pdgf signaling in lung explant cultures results in decreased Wnt signaling and lung smooth-muscle development. These data suggest a model in which Pdgf signaling potentiates Wnt2-Wnt7b signaling to promote high levels of Wnt activity in mesenchymal progenitors that is required for proper development of endoderm-derived organs, such as the lung.mesenchyme | epithelium

Modulation of apical constriction by Wnt signaling is required for lung epithelial shape transition

“…It has been reported that the β-catenin pathway is involved in the proximal-distal specification of lung epithelium by suppressing the expression of Sox2, a proximal airway marker (Hashimoto et al, 2012;Miller et al, 2012). In lung epithelium culture, CHIR99021 treatment decreased and increased mRNA levels of Sox2 and the distal progenitor marker SOX9 (Chang et al, 2013), respectively (Fig.…”

“…Wnt2 and Wnt7b are cooperatively required for the mesenchymal β-catenin pathway in cultured cell lines and their simultaneous knockout causes defects in branching morphogenesis and proximal-distal specification (Miller et al, 2012). The β-catenin pathway is consistently activated in the distal endodermal tip and surrounding mesenchyme during the early stage of lung development, as observed in a reporter gene-expressing murine model (Al Alam et al, 2011), and is required for branching morphogenesis (De Langhe et al, 2005;Miller et al, 2012) as well as distal progenitor maintenance (Mucenski et al, 2003). Although these studies reveal the importance of Wnt signaling in lung development, it remains unclear how the β-catenin pathway is involved in epithelial cell morphogenesis during lung development.…”

Epithelial Wnt Ligands Regulate Pulmonary Vasculature Development

“…There is an interesting explanation of noncanonical Wnts inducing canonical Wnt signaling: multiple Wnts might act in a combination [27,28]. In fact, the canonical Wnt, Wnt7b was also shown to cooperate with Wnt2 to promote foregut organogenesis [29]. All these complex interactions between Wnt ligands might lead to different observations, in some cases contradictory.…”

Wnt7b and Its Direct Target p57kip2 in Renal Medulla Development

“…Wnt7b is a Wnt family ligand important for the proper formation of a number of organs and tissues including the placenta, the eye, the bones, the lungs, the kidney, the central nervous system (CNS), neurons, hair, the pancreas, and olfactory receptor neuron axon connectivity. 70,166,[168][169][170][172][173][174][175][176][177][178][179][180][181][182] Notably, Wnt7b has been reported to regulate vasculature development in the eyes, the brain, and the lungs, by different cellular mechanisms. In the eye, it signals to the endothelial cells of the hyaloid vasculature and activates their apoptosis.…”

“…70,166,[168][169][170][172][173][174][175][176][177][178][179][180][181][182] In the kidney, Wnt7b is required for renal medulla formation. It promotes LOH elongation, regulates oriented cell division and elongation of the UB epithelium, inhibits proliferation in the peri-UB vasculature, and promotes peri-UB capillary formation.…”