lung development

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

size varies as a regular fraction of overall dimension is predicts average airway diameter will decrease at a regular rate irrespective of scale

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

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

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

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

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

distal epithelium and it is absent from the cleft during branching

cells growth responses along the airway tube low FGF10 = epithelial maturation, functional differentiation and slow proliferation high FGF10 = rapid proliferative growth and lube elongation

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

ERK1/2 activation and controls mitotic spindle angle thus the direction of tube growth close to FGF10 = tubule elongation distant from FGF10 = tubule branching

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

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

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

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