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Fig. 3. Models of bud formation and proximodistal patterning in the developing
lung. A developing lung bud during branching morphogenesis. Mesenchyme is
depicted in gray and the epithelium in blue or red (distal bud). (A)
Branching initiates with local Fgf10 expression in the distal
mesenchyme. Fgf10 diffuses (yellow arrow) and binds locally to Fgfr2b
(expressed throughout the lung epithelium) to activate signaling and induce a
bud (white arrow). (B) As the bud elongates, Fgfr2b signaling induces
expression of Spry2 (which negatively regulates Fgf signaling and
inhibits budding, broken yellow line) and Bmp4 in the distal
epithelium. Bmp4 possibly also inhibits distal budding through autocrine
signaling from the epithelium (Eblaghie et
al., 2006) (broken yellow line) and can also enhance budding in a
paracrine fashion (broken yellow arrow), via an unidentified mesenchymal
signal (X). Mesenchymal Pod1 (Tcf21) (indirectly) and epithelial Wnt signaling
regulate Bmp4 (see F). Mechanisms that might inhibit ectopic budding in stalk
regions include: netrin-mediated Fgfr2b signaling inhibition (broken yellow
line); Tgfb activation in the epithelium by Tgfb1 from the subepithelial
mesenchyme; Tgfb1-induced synthesis of extracellular matrix (ECM) components,
such as collagen and fibronectin, and Tgfbi in stalk mesenchyme. (C)
Control of Fgf10 and Fgfr2b expression. Canonical Wnt
signaling activates Fgfr2b expression in the lung epithelium;
mesenchymal Wnt (alone or with epithelial Wnt) inhibits Fgf10.
Positive regulators of Fgf10 include Foxf1, Tbx4 and Tbx5. Tgfb1
signaling in stalk mesenchyme may prevent Fgf10 expression in the
proximal mesenchyme (box in C). Shh signaling in the distal mesenchyme
inhibits Fgf10 expression, but via Gli3 also controls availability of
Foxf1, a positive regulator of Fgf10. Shh induction of Hhip
expression inhibits Shh signaling (broken yellow line) to allow Fgf10
expression. (D) At the bud tips, high Shh (distal epithelium) and Hhip
(distal mesenchyme) levels result in overall less Shh signaling and more
Fgf10 than in the immediately adjacent regions, where Shh signaling
is unopposed by Hhip. Low Shh levels in more proximal bud regions allow
Fgf10 expression in the adjacent mesenchyme, resulting in later
induction of lateral buds. (E) The proliferation of multipotent
mesenchymal progenitors while the lung grows depends on Shh and Wnt7b signals
from the distal epithelium and on Fgf9 from the pleura (purple). Foxa1 and
Foxa2 regulate Shh and Wnt7b expression. Vegf regulates
endothelial cell differentiation. RA (from the pleura) may regulate
Fgf9 expression but this remains to be shown. (F) A model of
proximodistal cell fate regulation in the lung bud epithelium. Mycn and Fgf10
(via Fgfr2b epithelial signaling) maintain the proliferation of progenitor
cells of the distal lung epithelium. Bmp4 prevents distal epithelial
cells from assuming a proximal phenotype. Wnt signaling regulates the timing
of their differentiation (presumably by controlling Bmp4 and
Mycn expression) and is negatively regulated by dickkopf 1 (Dkk1).
Foxj1 induces differentiation of proximal epithelium into ciliated cells. See
text for references and Eblaghie et al.
(Eblaghie et al., 2006).
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