Tissue Development, Repair, and Remodeling - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 681

Bone Morphogenetic Proteins

Bone morphogenetic proteins intervene in lung development, in particular in the
proximal-distal patterning. Isotype BMP4 is highly produced by epithelial cells of
bud tips and, to a lesser extent, in the surrounding mesenchyme [ 1396 ]. It precludes
epithelial cell proliferation.

11.3.2.2 Guidance Cues

Members of the netrin and semaphorin families participate in budding and branching
during lung morphogenesis. Netrin-1 and -4 are produced by epithelial cells of
bud stalks. They are deposited in the surrounding basement membrane, where they
preclude ectopic budding and inappropriate lateral branching [ 1395 ]. Both netrin-1
and -4 are expressed at their highest levels at non-branching proximal endoderm and
stalk region of growing buds. On the other hand, they are excluded from growing
bud tips, where most of the branching occurs. The spatial restriction of netrins
permits efficient branching genesis. In addition, netrin-4 and, to a lesser extent,
netrin-1 inhibit the formation of secondary buds induced by FGF7 or FGF10 [ 1395 ].
Semaphorin-3A is expressed by the mesenchyme that surrounds the ends of buds.
It organizes the size and shape of the emerging buds.

11.3.2.3 Wnt Morphogens

Wnt morphogens signal in progenitor cells of the respiratory epithelium both during
development and after injury. Activation of -catenin leads to its translocation

to the nucleus and formation of a transcriptional activation complex with either
T-cell factor (TCF), sex-determining region Y (SRY)-box gene product Sox9, or
pituitary (or Paired-like) homeobox transcription factors Pitx1 and Pitx2 to cause
the transcription of target genes, such as neuroblastoma-derived MYC (NMYC),
Bmp4, and Fgfr2b in epithelial cells, and MYC, PITX2, and Fgfr2c in mesenchymal
cells [ 1397 ]. Once bound to the mesenchymal fibroblast growth factor FGF10,
FGFR2b receptor triggers the

β

-catenin pathway. In the mesenchyme, mesothelial
and epithelial fibroblast growth factor FGF9 connects to FGFR2c to also initiate
the

β

-Catenin in the mesenchyme controls the differentiation of
angioblasts into endothelial cells as well as proliferation of parabronchial smooth
muscle progenitors [ 1397 ].
β

β -catenin pathway. β

-Catenin reduces the expression of epithelial differentiation markers during the
early pseudoglandular stage of lung development [ 1397 ]. During early lung devel-
opment, -catenin signaling triggers the proliferation of epithelial differentiation

marker-negative (surfactant protein SPc

β

) 4 cells that − and secretoglobin ScGb1a1 −

4 A.k.a. 10-kDa Clara cell phospholipid-binding secretory protein CC10.