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. Author manuscript; available in PMC: 2015 Feb 4.
Published in final edited form as: Nat Rev Mol Cell Biol. 2014 Dec;15(12):786–801. doi: 10.1038/nrm3904

Figure 3. Extracellular matrix remodelling during branching morphogenesis.

Figure 3

A| Ductal elongation and branching of the mammary and submandibular glands. Aa | Collagen is locally synthesized and aligned to increase extracellular matrix (ECM) stiffness and create a mechanical anisotropy that will drive branching. Collagen synthesis is mediated by the activation of the RHOA–RHO-associated protein kinase (ROCK) signalling pathway. The ECM at the end bud tip is much thinner than in cleft region and around the duct. Matrix metalloproteinase 2 (MMP2) and MMP14 are expressed and active at the end bud tip, whereas MMP3 is involved inside branching. Ab | Cleft formation and deepening in the submandibular glands. Fibronectin is locally assembled in the basement membrane and induces BTBD7 at the base of forming clefts, which in turn upregulates the transcription factor SNAIL2 and downregulates the adhesion molecule E-cadherin. These molecular events promote alterations in cell shape, decreasing cell–cell adhesion and promoting a motile phenotype to promote cleft progression. Fibronectin assembly requires focal adhesion kinase (FAK) activation and RHOA–ROCK-mediated actomyosin contraction. B | Role of elastin and collagen deposition in alveolar branching in the lung. Elastin and collagen deposition promotes ECM stiffness in the neonatal lung and facilitates signalling through the endothelial lipoprotein receptor-related protein 5 (LRP5)–TIE2 (also known as angiopoietin 1 receptor) pathway, which is required for normal lung development. Consistent with this, disrupting lung collagen I, III and VI and elastin expression and localization through treatment with β-aminopropionitrile, an inhibitor of the collagen crosslinking enzyme lysyl oxidase (LOX), softens neonatal mouse lung tissue and downregulates the expression of LRP5 and TIE2, which leads to an inhibition of vascular and alveolar morphogenesis in neonatal mice. Ca | Heparan sulphate proteoglycans (HSPGs) bind fibroblast growth factors (FGFs) with different affinity and help to create a concentration gradient that can control cell fate in submandibular glands. In contrast to FGF10, FGF7 binds HSPG with low affinity and diffuses broadly, promoting branching in the submandibular gland. Cb| HSPGs such as perlecan bind FGF10 with high affinity. Following cleavage by heparanase, perlecan releases FGF10, which can then diffuse locally and promote duct elongation. FGFR2, FGF receptor 2; MLC, myocin light chain; MYPT, myosin phosphatase. Figure part Ca modified from Differential interactions of FGFs with heparin sulfate control gradient formation and branching morphogenesis. Sci. Signal. Volume 2. Issue 88. Page ra55. 2009. Reprinted with permission from AAAS.