Comparative mechanisms of branching morphogenesis in diverse systems

Abstract

Much progress has been made in recent years toward understanding mechanisms controlling branching morphogenesis, a fundamental aspect of development in a variety of invertebrate and vertebrate organs. To gain a deeper understanding of how branching morphogenesis occurs in the mammary gland, we compare and contrast the cellular and molecular events underlying this process in both invertebrate and vertebrate organs. Thus, in this review, we focus on the common themes that have emerged from such comparative analyses and discuss how they are implemented via a battery of signaling pathways to ensure proper branching morphogenesis in diverse systems.

Figure 1

Fate map of the tip and duct of branching renal epithelium. a. Relative contribution of the tip and duct to ductal elongation. The overall increase of ductal length during renal epithelial invasion is the sum of new ductal epithelium produced by extension of the existing duct (light gray) and by derivation from the tip (dark gray), b. Ductal participation in the remodeling of a branch-point. As the tip bifurcates and gives rise to two new tips. The original ductal epithelium is remodeled so that it contributes to the proximal side of each new trunk, whereas the rest of the trunk epithelium derives from each new tip. Ed, ductal contribution of elongation; Et, tip contribution of elongation; En, net increase of ductal length. Adapted from Shakya et al. [25].

Figure 2

Differential RTK signaling pathways control cell proliferation and migration in Drosophila tracheal air sac. Coordination of cell behavior in the outgrowth of a fly larval tracheal air sac. FGF signaling is required for migration of cells at the leading edge. Bnl/Fgf ligands are expressed in the cells adjacent (dark gray cloud) to the tracheal epithelium. Activation of Btl/Fgfr function in cells at the leading edge (gray) triggers changes in the cytoskeleton and cell shapes, and thus causes cells to migrate toward the source of signal. EGF signaling is required for all epithelial cells to proliferate and/or to survive and thus plays a permissive role in air sac outgrowth. Although sharing major downstream effectors, these two RTKs use different molecules to ensure distinct cellular effects. Adapted from Cabernard and Affolter [35].

Figure 3

Common themes controlling branching morphogenesis in diverse organs. The mesenchyme produces guidance cues (Gm) and survival factors (Sm) for the epithelium during branching morphogenesis. The epithelium responses to these mesenchymal factors, via an unknown mechanism (dotted arrow and question mark), by making survival factors (Se) for the mesenchyme. In addition, the epithelium produces factors (Me) that can modulate the activities of factors produced by the mesenchyme (via an unknown mechanism, dotted arrow and question mark). The epithelium adjusts its responsiveness by expressing Re and fine-tuning its sensitivity to mesenchymal inputs. Conversely, the mesenchyme adjusts its responsiveness (Rm) to epithelial inputs. Epi, epithelium; Gm, mesenchymal guidance cues; Me, epithelial modulators; Mes, mesenchyme; Re, epithelial responsiveness; Rm, mesenchymal responsiveness; Se, epithelial survival factors; Sm, mesenchymal survival factors.