Abstract
The cellular and molecular cues involved in creating branched tubular networks that transport liquids or gases throughout an organism are not well understood. To identify factors required in branching and lumen formation of Drosophila tracheal terminal cells, a model for branched tubular networks, we performed a forward genetic-mosaic screen to isolate mutations affecting these processes. From this screen, we have identified the first Drosophila mutation in the gene Zpr1 (Zinc finger protein 1) by the inability of Zpr1-mutant terminal cells to form functional, gas-filled lumens. We show that Zpr1 defective cells initiate lumen formation, but are blocked from completing the maturation required for gas filling. Zpr1 is an evolutionarily conserved protein first identified in mammalian cells as a factor that binds the intracellular domain of the unactivated epidermal growth factor receptor (EGFR). We show that down-regulation of EGFR in terminal cells phenocopies Zpr1 mutations and that Zpr1 is epistatic to ectopic lumen formation driven by EGFR overexpression. However, while Zpr1 mutants are fully penetrant, defects observed when reducing EGFR activity are only partially penetrant. These results suggest that a distinct pathway operating in parallel to the EGFR pathway contributes to lumen formation, and this pathway is also dependent on Zpr1. We provide evidence that this alternative pathway may involve fibroblast growth factor receptor (FGFR) signaling. We suggest a model in which Zpr1 mediates both EGFR and FGFR signal transduction cascades required for lumen formation in terminal cells. To our knowledge, this is the first genetic evidence placing Zpr1 downstream of EGFR signaling, and the first time Zpr1 has been implicated in FGFR signaling. Finally, we show that down-regulation of Smn, a protein known to interact with Zpr1 in mammalian cells, shows defects similar to Zpr1 mutants.
Highlights
Branched tubular networks, such as the vascular and respiratory systems, are a common structural design used to facilitate the transport of liquids and gases throughout the body
We find that all Zinc finger protein 1 (Zpr1) homozygous mutant cells overexpressing lbtl display a Zpr1-like phenotype (Fig. 3F, F’), indicating that Zpr1 is epistatic to fibroblast growth factor receptor (FGFR) overexpression in terminal cell lumen formation
To achieve complete interconnectivity the Drosophila tracheal system undergoes extensive branching and fusion steps beginning in embryogenesis and continuing throughout larval development [2]
Summary
Branched tubular networks, such as the vascular (blood) and respiratory systems, are a common structural design used to facilitate the transport of liquids and gases throughout the body. The larval tracheal system is composed of a network of approximately 10,000 interconnected tubes that serve to transport oxygen and other gases throughout the body [1,2] To construct this elaborate tubular network, cells within the tracheal epithelium first undergo a series of coordinated and stereotyped branching and tubulogenesis events during mid-embryogenesis. These events are primarily regulated by a fibroblast growth factor ligand (FGF) and receptor (FGFR), encoded by the branchless (bnl) and breathless (btl) genes, respectively [3,4]. Terminal cells may provide a model for understanding the development of fine capillaries within the vertebrate vasculature whose development depends on tissue oxygen status [13]
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