Journal
CURRENT BIOLOGY
Volume 14, Issue 10, Pages 897-905Publisher
CELL PRESS
DOI: 10.1016/j.cub.2004.05.020
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Funding
- NHLBI NIH HHS [R01 HL071303, R37 HL071303, HL71303-11] Funding Source: Medline
- NINDS NIH HHS [NS 039502, R01 NS039502, R01 NS039502-04] Funding Source: Medline
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The development of many organs, including the lung, depends upon a process known as branching morphogenesis, in which a simple epithelial bud gives rise to a complex tree-like system of tubes specialized for the transport of gas or fluids. Previous studies on lung development have highlighted a role for fibroblast growth factors (FGFs), made by the mesodermal cells, in promoting the proliferation, budding, and chemotaxis of the epithelial endoderm [1-3]. Here, by using a three-dimensional culture system, we provide evidence for a novel role for Netrins, best known as axonal guidance molecules [4, 5], in modulating the morphogenetic response of lung endoderm to exogenous FGFs. This effect involves inhibition of localized changes in cell shape and phosphorylation of the intracellular mitogen-activated protein kinase(s) (ERK1/2, for extracellular signal-regulated kinase-1 and -2), elicited by exogenous FGFs. The temporal and spatial expression of netrin 1, netrin 4, and Unc5b genes and the localization of Netrin-4 protein in vivo suggest a model in which Netrins in the basal lamina locally modulate and fine-tune the outgrowth and shape of emergent epithelial buds.
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