grants and publications

Genetic Control of Branching Morphogenesis

Metzger R.J., Krasnow MA. Science  284,1635-9. 04 Jun 1999


The genetic programs that direct formation of the treelike branching structures of two animal organs have begun to be elucidated. In both the developing Drosophila tracheal (respiratory) system and mammalian lung, a fibroblast growth factor (FGF) signaling pathway is reiteratively used to pattern successive rounds of branching. The initial pattern of signaling appears to be established by early, more global embryonic patterning systems. The FGF pathway is then modified at each stage of branching by genetic feedback controls and other signals to give distinct branching outcomes. The reiterative use of a signaling pathway by both insects and mammals suggests a general scheme for patterning branching morphogenesis.

The branching programme of mouse lung development.

Metzger, R.J., Klein, O., Martin, G.R. & Krasnow, M.A. Nature 453, 745-450. 2008


Mammalian lungs are branched networks containing thousands to millions of airways arrayed in intricate patterns that are crucial for respiration. How such trees are generated during development, and how the developmental patterning information is encoded, have long fascinated biologists and mathematicians. However, models have been limited by a lack of information on the normal sequence and pattern of branching events. Here we present the complete three-dimensional branching pattern and lineage of the mouse bronchial tree, reconstructed from an analysis of hundreds of developmental intermediates. The branching process is remarkably stereotyped and elegant: the tree is generated by three geometrically simple local modes of branching used in three different orders throughout the lung. We propose that each mode of branching is controlled by a genetically encoded subroutine, a series of local patterning and morphogenesis operations, which are themselves controlled by a more global master routine. We show that this hierarchical and modular programme is genetically tractable, and it is ideally suited to encoding and evolving the complex networks of the lung and other branched organs.

Control of mitotic spindle angle by the RAS-regulated ERK1/2 pathway determines lung tube shape.

Tang, N., Marshall W.F., McMahon M., Metzger R.J. & Martin, G.R. Science 333, 342-345. 2011


During early lung development, airway tubes change shape. Tube length increases more than circumference as a large proportion of lung epithelial cells divide parallel to the airway longitudinal axis. We show that this bias is lost in mutants with increased extracellular signal–regulated kinase 1 (ERK1) and ERK2 activity, revealing a link between the ERK1/2 signaling pathway and the control of mitotic spindle orientation. Using a mathematical model, we demonstrate that change in airway shape can occur as a function of spindle angle distribution determined by ERK1/2 signaling, independent of effects on cell proliferation or cell size and shape. We identify sprouty genes, which encode negative regulators of fibroblast growth factor 10 (FGF10)–mediated RAS-regulated ERK1/2 signaling, as essential for controlling airway shape change during development through an effect on mitotic spindle orientation.

Multiple roles and interactions of Tbx4 and Tbx5 in development of the respiratory system. 

Arora R., Metzger R.J., Papaioannou V.E. PLoS Genetics 8, e1002866. 2012

Host cell polarity proteins participate in innate immunity to Pseudomonas aeruginosa infection.

Tran C.S., Eran Y., Ruch T.R., Bryant D.M., Datta A., Brakeman P., Kierbel A., Wittmann T., Metzger R.J., Mostov K.E., & Engel J.N. Cell Host Microbe 15, 636-642. 2014