Molecular Mechanisms of Early Lung Specification and Branching Morphogenesis

Warburton, David; Bellusci, Savério; Langhe, Stijn De; Moral, Pierre-Marie del; Fleury, Vincent; Mailleux, Arnaud; Tefft, Denise; Unbekandt, Mathieu; Wang, Kasper; Shi, Wei

doi:10.1203/01.pdr.0000159570.01327.ed

Cited by 198 publications

(200 citation statements)

References 149 publications

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“…With the lineage in hand, functions can now be assigned with unprecedented precision to the dozens of extant lung development genes 18,[31][32][33][34] . We found that Spry2 regulates the site of initiation and number of branches in specific domains (P1, Fig.…”

Section: Elucidating the Genetic Basis Of The Branching Programmentioning

confidence: 99%

The branching programme of mouse lung development

Metzger

Klein

Martin

et al. 2008

Nature

705

786

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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 program is genetically tractable, and it is ideally suited to encoding and evolving the complex networks of the lung and other branched organs.Many organs are composed of highly ramified tubular networks, each with a distinct architecture tailored to its physiological function. The bronchial tree of the human lung has over 10 5 conducting and 10 7 respiratory airways arrayed in an intricate pattern crucial for oxygen flow [1][2][3][4] . Classical studies of lung structure 5-8 raise the question of how the information required to generate a tree of such complexity is biologically encoded 9 . Individually configuring thousands or millions of branches would require a tremendous amount of patterning information, far more than is biologically plausible, to specify when and where each branch forms during development, and the size, shape, and direction of outgrowth of each branch. One possibility is that the process is not precisely controlled, for example if branching occurs randomly to fill available space. Another is that control is precise but coding is simplified by repeated use of a branching mechanism, as in Mandelbrot's fractal model and other elegant algorithms [10][11][12][13][14][15][16][17] . Even with these attractive models and recent progress in identifying lung development genes 18 , understanding of the program that directs branching remains rudimentary. This is largely due to the complexity of the bronchial tree, which makes it difficult to follow branching dynamics beyond the earliest events [19][20][21] . Although branching of the lung and other organs can occur in culture [22][23][24][25] , it is unlikely these recapitulate the full pattern. Here, we have determined the complete in vivo pattern of branching and branch lineage of the mouse bronchial tree, and show that it is generated using three geometrically distinct local modes of branching coupled in three different sequences. The branch lineage of the mouse bronchial treeThe bronchial tree develops by bran...

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Section: Elucidating the Genetic Basis Of The Branching Programmentioning

confidence: 99%

The branching programme of mouse lung development

Metzger

Klein

Martin

et al. 2008

Nature

705

786

View full text Add to dashboard Cite

show abstract

“…(49) Instead, Sprouty1 appears to regulate the response to GDNF. While in other developing organs such as the lung, Sprouty proteins regulate the response to FGFs, (50) the urogenital defects in Sprouty1 À/À embryos seem to be caused by a failure to regulate the GDNF pathway, because they can be rescued by reducing the GDNF gene dosage. Furthermore, Sprouty1 expression is reduced in Ret þ/À embryos, and is upregulated by added GDNF, suggesting a negative feedback loop.…”

Section: The Role Of Localized Gdnf/ret Signaling In Ureter Formationmentioning

confidence: 99%

GDNF/Ret signaling and the development of the kidney

2006

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SummarySignaling by GDNF through the Ret receptor is required for normal growth of the ureteric bud during kidney development. However, the precise role of GDNF/Ret signaling in renal branching morphogenesis and the specific responses of ureteric bud cells to GDNF remain unclear. Recent studies have provided new insight into these issues. The localized expression of GDNF by the metanephric mesenchyme, together with several types of negative regulation, is important to elicit and correctly position the initial budding event from the Wolffian duct. GDNF also promotes the continued branching of the ureteric bud. However, it does not provide the positional information required to specify the pattern of ureteric bud growth and branching, as its site of synthesis can be drastically altered with minimal effects on kidney development. Cells that lack Ret are unable to contribute to the tip of the ureteric bud, apparently because GDNF-driven proliferation is required for the formation and growth of this specialized epithelial domain.

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“…The organ that is most often compared to the developing Drosophila tracheal system is the mammalian lung (Cardoso and Lu, 2006;Hogan and Kolodziej, 2002;Warburton et al, 2005). The finding that Fgf10 is expressed in a dynamic fashion at branch tips in the mammlian lung and is intimately linked to the branching process has highlighted that molecular similarities exist between branching in the mammalian lung and the insect trachea (Bellusci et al., 1997;Sekine et al, 1999;De Moerlooze et al, 2000).…”

Section: Do General Cellular Principles Underlie Branching Morphogenementioning

confidence: 99%

Tracheal branching morphogenesis inDrosophila: new insights into cell behaviour and organ architecture

2008

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2055Our understanding of the molecular control of morphological processes has increased tremendously over recent years through the development and use of high resolution in vivo imaging approaches, which have enabled cell behaviour to be linked to molecular functions. Here we review how such approaches have furthered our understanding of tracheal branching morphogenesis in Drosophila, during which the control of cell invagination, migration, competition and rearrangement is accompanied by the sequential secretion and resorption of proteins into the apical luminal space, a vital step in the elaboration of the trachea's complex tubular network. We also discuss the similarities and differences between flies and vertebrates in branched organ formation that are becoming apparent from these studies. IntroductionBranching morphogenesis restructures epithelial sheets to give rise to organs of fascinating three-dimensional architecture, as exemplified by the adult lung, the kidney and the vasculature in humans. In Drosophila melanogaster, genetic studies have provided much insight into the regulatory networks that regulate the ordered formation of tracheal branches in the embryo, and into how the different branches coordinate their relative sizes, an issue that is of importance to the physical aspects of branched organ function (Affolter et al., 2003;Ghabrial et al., 2003;Uv et al., 2003). More recently, the development of live-imaging approaches in Drosophila have allowed researchers to take a deeper look at the behaviour of cells during the branching process, and have enabled events at the molecular level to be linked to the behaviour of individual cells or groups of cells.This combination of molecular genetics and live-imaging techniques has provided investigators with a unique opportunity to understand the morphological processes that occur during branching morphogenesis. This review focuses and builds on some of these recent insights, and assesses how they have led to a better understanding of the cellular and molecular processes that contribute to the transformation of simple, two-dimensional epithelial sheets into fascinating, three-dimensional tubular structures that can perform important functions in development and homeostasis. We focus here on the Drosophila tracheal system because several cellular and molecular paradigms, such as cell migration, competition and rearrangement, as well as the elaboration of a complex apical luminal environment, have recently been uncovered in this system that might serve related roles in the formation of other branched organs or tissues; these similarities might help us in the future to gain an even better understanding of how morphogenesis in general is regulated during development. Tracheal development in the fly embryoThe complex structure of the tracheal system consists of interconnected, metameric units of different-sized tubes that extend over the entire embryo shortly before hatching (Samakovlis et al., 1996b) (see Fig. 1, see also Movie 1 in the supplementary material)....

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Molecular Mechanisms of Early Lung Specification and Branching Morphogenesis

Cited by 198 publications

References 149 publications

The branching programme of mouse lung development

The branching programme of mouse lung development

GDNF/Ret signaling and the development of the kidney

Tracheal branching morphogenesis inDrosophila: new insights into cell behaviour and organ architecture

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