Novel Role for Netrins in Regulating Epithelial Behavior during Lung Branching Morphogenesis

Abstract

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. Here, by using a three-dimensional culture system, we provide evidence for a novel role for Netrins, best known as axonal guidance molecules, 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.

Overexpression of Netrin-1 Induces Neovascularization in the Adult Mouse Brain

“…Endogenous netrin-1, predominantly expressed by the floor plate cells in the central nervous system, induces axonal outgrowth, axonal orientation, and neuronal migration during neuronal development (Barallobre et al, 2005;Xie et al, 2006). Besides the aforementioned roles it plays in the central nervous system, NT-1 has also been implicated in regulating salivary gland migration (Kolesnikov and Beckendorf, 2005), regulating invasion and migration of mouse mammary epithelial cells (Strizzi et al, 2005), promoting lung branching morphogenesis (Liu et al, 2004), and mediating pancreatic epithelial cell adhesion (Hebrok and Reichardt, 2004). Further, netrin-1 can stimulate the proliferation and migration of human microvascular endothelial cells, and induce angiogenesis on chorioallantoic membrane and murine cornea in vivo (Park et al, 2004).…”

The building blocks of mammalian lung development

“…The work of many laboratories has suggested that these cells are a multipotent epithelial progenitor population (reviewed in Cardoso and Lu, 2006). Compared with the epithelial stalk cells, the distal tip cells have a unique pattern of gene expression including high levels of Bmp4, Shh, Nmyc, Sox9, Id2, and Etv4/5 (reviewed in Rawlins, 2008), faster cell cycle kinetics (Okubo et al, 2005), and a subtly different morphology (Liu et al, 2004). Moreover, lung epithelial-specific deletion, or overexpression, of Nmyc results in phenotypes consistent with a premature loss, or overproliferation, of epithelial progenitor cells (Okubo et al, 2005).…”

Axon guidance factor netrin-1 and its receptors regulate angiogenesis after cerebral ischemia

“…Netrin-1 was the first to be purified and is the best-characterized member. In addition to its involvement in guiding axon migration during embryonic development, netrin-1 functions in organ formation [3][4][5][6] , tumorigenesis [7] , inflammation [8,9] , and anti-apoptotis [10] , as well as being a potential biomarker for renal injury and certain cancers [11,12] . It also promotes the recovery of neuronal function after cerebral ischemia in animal models [13][14][15][16] .…”