Drosophila as a model for epithelial tube formation - PubMed
Review
. 2012 Jan;241(1):119-35.
doi: 10.1002/dvdy.22775. Epub 2011 Nov 14.
Affiliations
- PMID: 22083894
- PMCID: PMC3922621
- DOI: 10.1002/dvdy.22775
Review
Drosophila as a model for epithelial tube formation
Rika Maruyama et al. Dev Dyn. 2012 Jan.
Abstract
Epithelial tubular organs are essential for life in higher organisms and include the pancreas and other secretory organs that function as biological factories for the synthesis and delivery of secreted enzymes, hormones, and nutrients essential for tissue homeostasis and viability. The lungs, which are necessary for gas exchange, vocalization, and maintaining blood pH, are organized as highly branched tubular epithelia. Tubular organs include arteries, veins, and lymphatics, high-speed passageways for delivery and uptake of nutrients, liquids, gases, and immune cells. The kidneys and components of the reproductive system are also epithelial tubes. Both the heart and central nervous system of many vertebrates begin as epithelial tubes. Thus, it is not surprising that defects in tube formation and maintenance underlie many human diseases. Accordingly, a thorough understanding how tubes form and are maintained is essential to developing better diagnostics and therapeutics. Among the best-characterized tubular organs are the Drosophila salivary gland and trachea, organs whose relative simplicity have allowed for in depth analysis of gene function, yielding key mechanistic insight into tube initiation, remodeling and maintenance. Here, we review our current understanding of salivary gland and trachea formation - highlighting recent discoveries into how these organs attain their final form and function.
Copyright © 2011 Wiley Periodicals, Inc.
Figures

(Left) Salivary gland-specific gene expression is first observed in embryonic stage 10 when the salivary placodes form. Invagination of the salivary gland begins during embryonic stage 11 to create an internalized epithelial tube. During embryonic stage 12, the salivary tube elongates, turns and begins its posterior migration. The salivary glands arrive at their final correct positions during the late embryonic stages. (Right) Tracheal-specific gene expression is first observed in embryonic stage 9 when the tracheal placodes form. Invagination of the trachea begins during embryonic stage 10 as the cells undergo their final mitotic division. During embryonic stage 12, the primary branches form and begin their stereotypic migration. Beginning at embryonic stage 14, the major branches of the trachea fuse with those of their anterior, posterior and contralateral neighbors. During the final stages of embryogenesis, the terminal branches develop and contact target tissues. Just prior to hatching, the tracheal lumen is cleared of solids and liquids, and fills with gas.

(Top pathway) Scr, Exd and Hth work together to specify the SG fate in parasegment 2 (PS2) by activating expression of several early-expressed genes, including the transcription factors Hkb, Sage, Fkh and CrebA. SG formation is limited to a subset of cells within PS2 by dorsal Dpp signaling. The ventral ectodermal cells of PS2 are specified as salivary duct through ventral EGF-signaling. Although global expression of Scr can drive formation of ectopic SGs in more anterior parasegments (PS0, PS1), it fails to induce SG fates in more posterior segments because of the activities of the trunk gene Tsh (PS3-13) and Hox gene Abd-B (PS14). (Bottom pathway) Whereas Hkb is only transiently expressed in the SG, Sage, Fkh and CrebA continue to be expressed in the SGs where they function to maintain and implement the earlier decision to form SGs. Fkh has many roles in the SG, including maintaining its own expression and that of Sage and CrebA. Fkh also controls invagination and is required for polytenization. Fkh keeps SG cells alive and works with Sage to control expression of genes required to maintain an open patent SG lumen. CrebA functions to increase secretory capacity by upregulating expression of the protein components of secretory machinery.

Embryos have been stained with αCrebA (red nuclear staining) and αSAS (green apical/lumenal staining). Left panels are low-magnification ventral or ventrolateral views of SGs of increasing age from top to bottom. Right panels are high magnification lateral or ventrolateral views of SGs of increasing age from top to bottom. The SG primordia are first apparent as two plates of cells on the ventral surface of PS2 (top left). Cells in a dorsolateral position of the primordia undergo apical constriction and invaginate into the embryo. At this point SAS staining becomes apparent on the apical lumenal surface (row 1, right image, and row 2, left image). As the cells continue to change shape and invaginate, an internalized cup-shaped tube is formed with the inside apical surface of the cup contiguous with the outside apical surface of the cells that remain to be internalized (row 2, right image). The SG moves in a dorsal-posterior trajectory until they contact the overlying visceral mesoderm, at which point, they reorient and begin active posterior migration (row 3, right panel, row 4, right panel). The proximal secretory tube and salivary duct invaginate and form tubes through a wrapping-type mechanism to fully internalize the organ by embryonic stage 15. At this stage, two elongated secretory tubes are connected to the larval mouth through the individual and common branches of the salivary duct. No cell death or division occurs and SG cells retain their polarized phenotype through the entire process of morphogenesis.

(Top pathway) JAK/STAT signaling specifies trachea by activating expression of early tracheal genes, including two transcription factors, Trh and Vvl. Trachea formation is limited to PS4 – 13 by early expression of Salm in more anterior and posterior parasegments. As with the SG, Dpp- and EGF-signaling provide dorsal and ventral limits on trachea specification. Wg functions within each segment to limit trachea formation to a subset of cells within each segment of the embryo. Trh maintains Upd expression in the trachea, where Upd is proposed function non-autonomously in the recruitment of additional cells within each segment to a tracheal fate. (Bottom pathway) Trh and Vvl continue to be expressed in the trachea to maintain and implement the decision to form trachea. Trh is required to not only maintain its own expression but is required for the expression of all tracheal genes. Vvl regulates only an estimated 25 – 30% of tracheal genes, including Rho and Btl, which function in tracheal invagination and migration. Among the early Trh targets is Kni, a transcription factor required to limit the domain of Salm, which in the trachea plays key roles in the types of tubes that form in the different tracheal branches.

Embryos in top three rows have been stained with αTrh (red nuclear staining), which is expressed throughout the trachea, and αKni (green nuclear staining), which has more dynamic and limited tracheal expression. The stage 12 tracheal metamere in the bottom right panel has been stained with Crumbs (green) and Rab11 (red). The stage 16 embryo in the bottom right panel has been stained with 2A12, a lumenal marker. There are ten tracheal metameres (tr1 – tr10), which begin as plates of polarized epithelial cells on the lateral surface of the trunk region of the embryo (top left panel). As cells undergo apical constriction and invaginate to form internalized tracheal sacs, they undergo their final mitotic division, resulting in ~80 cells per tracheal metamere (middle left panel). Subsets of cells in different positions in the internalized sacs subsequently migrate out to give rise to the different tracheal branches: TC (1), DT(2), VB (3), GB (4), LT (5) and DB(6) (top three right panels and bottom two panels). Cells at the ends of the DB, DT and VB will fuse with their contralateral or anterior or posterior neighbors to form a contiguous tubular network (bottom right panel).
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