lung development Flashcards
how are tubular structures of lungs packed into their confined space
through fractal geometry
approx 23 generations of airway branching
8km of combined airway length
300 m of alveoli
gas exchange surface area is 130m sq
combined vascular length is 2-6000 km
average distance travelled by gas - 25cm
tensile pressure needed to rupture the blood gas barrier = 0.5 MN.M-2
what is fractal geometry
size varies as a regular fraction of overall dimension
is predicts average airway diameter will decrease at a regular rate irrespective of scale
lung formation
the lungs forma s an out-pocketing of ventral foregut
(26 days- 6 weeks in humans, mouse e8-9.5)
E9 mouse - foregut is specified into organ specific domains , Nkx2.1-TrF is expressed in heart, respiratory and thyroid domains - first regulatory protein determining growth of respiratory tissue
E9.5 mouse - initial budding of trachea and lung
1. trachea buds from ventra-foregut endoderm
2. lung buds form from lateral foregut endoderm and extend laterally into adjacent mesoderm - basic buds of left and right lung
E11.5 mouse - trachea separates from the gut tube
1. trachea grows vetnrally and separates from the foregut
2. by 11.5 trachea and oesophagus are clearly separate stuctures
3. airways branching proceeds with 2 branched generations by e10.5 and 3 branched generations by e12, in mice 1 lobe to left lung and 4 to the right lung
lung cell fate specification in foregut
e8 - TFs Gata4, Gata6, Foxa1 aqnd Foxa2 regulate endodermal foregut tube closure
e8.5 - diffusion gradients of FGF1 and 2 emanate from the heart region
e9 - FGF isoforms indue Nkx2.1b expression in thyroid and respiratory tissue
what growth factor induces tubular outgrowth of lung
FGF10
induces growth factor signalling through TKR
FGFR2b expressed in epithelium of endodermal tube
mesenchyme induction of epithelial budding requires FGF1- signalling to FGFR2 in the lung
FGF10 increases and expands caudally as bud reaches the periphery
buds grow toward high FGF10, expression is offset from axis of primary airway growth
FGF and its receptors in fractal geometry
evolutionary conserved family of secreted polypeptide ligands consisting of 23 members
play a role in development of all species
secreted by specialised populations of mesoderm derived mesenchymal cells
site of action is on epithelial cells that line the ectoderm tube
- bind to heparan sulfates present on cell surface proteoglycans
- promote FGF receptor subunit dimerisation and activation - alternate splicing gives rise to different variants of receptor
controlling tube length and branching
FGF10 - FGFR2 - Sprouty2 periodicity clock
in drosophila, hyper longation of the tracheal tubule system is caused by unhindered signals from branchless to breathless
the sprouty gene antagonises this signalling and produces a normal branches tracheal airway
in mammals, sprouty2 gene function is an indenticle manner to control the length of the airway between branches and also the orientation of division
it acts as a molecular timing mechanism which regulates the relationship between FGF10, FGFR2b and sprouty2 explains fractal growth pattern in the airway
where is mSprouty2 restricted to
distal epithelium and it is absent from the cleft during branching
what does a gradient of FGF10 control
cells growth responses along the airway tube
low FGF10 = epithelial maturation, functional differentiation and slow proliferation
high FGF10 = rapid proliferative growth and lube elongation
does sprouty2 activity define cells growth patterns along the epithelial tube?
sprouty2 regulates signalling via ERK1 and 2 and mTOR to control airway cell maturation vs proliferation
level of ERK1/2 determines angle of cell differentiation
inhibition = longitudinal growth
activation = perpendicular cell division
what does sprouty2 regulate
ERK1/2 activation and controls mitotic spindle angle thus the direction of tube growth
close to FGF10 = tubule elongation
distant from FGF10 = tubule branching
foetal responses to mTOR and ERK1/2 activation
mTOR activation: - proliferation - induces protein synthesis - controls cell size - conserves stem cell phenotype - prevents differentiation ERK1/2 maturation: - direction of tube growth - induces phenotypic differentiation toward specific cell types - induces apical / basal cell polarity - specifies cell shape - induces channel assembly and promotes ion transport
how does sprouty2 inhibit signalling from FGFR2b to ERK1/2
FRS-2: Suc-1 associated neurotrophic factor target which functions as a lipid docking protein
on FGFR activation it binds and translocates signalling molecules to the lipid membrane
Grb2/Sos: catalyses GDP to GTP on Ras so enables Raf activation = activation of mitogen activated protein kinases ERK1 and 2, cell differentiation and direction of growth
inhibition of sprouty2 to grb2 inhibits ERK1/2 so no differentiation and growth orientation
how does Sprouty2 activate mTOR signalling
TSC1 and TSC2 are inhibitors of mTOR and work by holding a small g protein Rheb in its inactive GDP bound form
degradation of TSC1 and TSC2 enables Rheb to bind to GTP and activate mTOR
making the branch by splitting FGF10 signal
on sustained exposure to FGF10 genes are induced in the epithelium with a function in branching
Shh - secreted from the epithelium, inhibits FGF10 expression
Wnt/B-catenin - deposition of fibroconnectin in cleft
Dickopf - secreted from epithelium, local inhibition of Wnt signalling - directs site of fibroconnectin signalling
coordination of events = irregular Dichotomous branching pattern of the lung
