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Airway maturation in Drosophila
Stockholm University, Faculty of Science, The Wenner-Gren Institute .
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Tubes are a fundamental unit of organ design. Most of our major organs like the lung, kidney and vasculature are composed primarily of tubes. To identify fundamental biological principles of tubular organ formation we used the respiratory organ of Drosophila melanogaster, the trachea.This work dissects embryonic trachea maturation. Three precise epithelial transitions occur during airway maturation. A secretion burst deposits proteins into the lumen; then luminal material is cleared and finally liquid is removed. We identified the cellular mechanisms behind these transitions. Sar1 and γCOP are required for protein secretion, matrix assembly and tube expansion. Rab5-dependent endocytic activity internalizes and clears luminal contents. The data show how programmed transitions in cellular activities form functional airways, and may reflect a general mechanism in respiratory organ morphogenesis.We further focused on tube size regulation. We identified Melanotransferrin, a new component of septate junctions that limits tracheal tube elongation. MTf is a lipid- modified, iron-binding protein attached to epithelial cell membranes, similarly to its human homologue. We show that septate junction assembly during epithelial maturation relies on endocytosis and apicolateral recycling of iron-bound MTf. Mouse MTf complements the defects of Drosophila MTf mutants. This provides the first genetic model for the functional dissection of MTf in epithelial morphogenesis. In the last part, we describe two genes, which are selectively involved in tube diameter expansion. Obst-A and Gasp are closely related proteins with characteristic chitin-binding domains. They are strongly expressed in the trachea at the time of lumen expansion. The single and double mutants cause a tube diameter reduction, whereas their overexpression leads to its increase. We propose that Obst-A and Gasp organize luminal matrix assembly and thereby regulate the extent of tube diameter expansion.

Place, publisher, year, edition, pages
Stockholm: The Wenner-Gren Institute, Stockholm University , 2011. , 18 p.
National Category
Developmental Biology
Research subject
Developmental Biology
Identifiers
URN: urn:nbn:se:su:diva-62419ISBN: 978-91-7447-338-4. OAI: oai:DiVA.org:su-62419DiVA: diva2:441691
Public defence
2011-10-21, Högbomsalen, Geovetenskapens hus, Svante Arrhenius väg 12, 10:00 (English)
Opponent
Supervisors
Note
At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: Manuscript.Available from: 2011-09-29 Created: 2011-09-19 Last updated: 2011-09-29Bibliographically approved
List of papers
1. Sequential Pulses of Apical Epithelial Secretion and Endocytosis Drive Airway Maturation in Drosophila
Open this publication in new window or tab >>Sequential Pulses of Apical Epithelial Secretion and Endocytosis Drive Airway Maturation in Drosophila
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2007 (English)In: Developmental Cell, ISSN 1534-5807, E-ISSN 1878-1551, Vol. 13, no 2, 214-225 p.Article in journal (Refereed) Published
Abstract [en]

The development of air-filled respiratory organs is crucial for survival at birth. We used a combination of live imaging and genetic analysis to dissect respiratory organ maturation in the embryonic Drosophila trachea. We found that tracheal tube maturation entails three precise epithelial transitions. Initially, a secretion burst deposits proteins into the lumen. Solid luminal material is then rapidly cleared from the tubes, and shortly thereafter liquid is removed. To elucidate the cellular mechanisms behind these transitions, we identified gas-filling-deficient mutants showing narrow or protein-clogged tubes. These mutations either disrupt endoplasmatic reticulum-to-Golgi vesicle transport or endocytosis. First, Sar1 is required for protein secretion, luminal matrix assembly, and diametric tube expansion. Subsequently, a sharp pulse of Rab5-dependent endocytic activity rapidly internalizes and clears luminal contents. The coordination of luminal matrix secretion and endocytosis may be a general mechanism in tubular organ morphogenesis and maturation.

National Category
Developmental Biology
Research subject
Developmental Biology
Identifiers
urn:nbn:se:su:diva-32568 (URN)10.1016/j.devcel.2007.06.008 (DOI)000248664300009 ()
Available from: 2009-12-14 Created: 2009-12-14 Last updated: 2017-12-12Bibliographically approved
2. COPI Vesicle Transport Is a Common Requirement for Tube Expansion in Drosophila
Open this publication in new window or tab >>COPI Vesicle Transport Is a Common Requirement for Tube Expansion in Drosophila
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2008 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 09 AprArticle in journal (Refereed) Published
Abstract [en]

Background Tube expansion defects like stenoses and atresias cause devastating human diseases. Luminal expansion during organogenesis begins to be elucidated in several systems but we still lack a mechanistic view of the process in many organs. The Drosophila tracheal respiratory system provides an amenable model to study tube size regulation. In the trachea, COPII anterograde transport of luminal proteins is required for extracellular matrix assembly and the concurrent tube expansion.

Principal Findings We identified and analyzed Drosophila COPI retrograde transport mutants with narrow tracheal tubes. γCOP mutants fail to efficiently secrete luminal components and assemble the luminal chitinous matrix during tracheal tube expansion. Likewise, tube extension is defective in salivary glands, where it also coincides with a failure in the luminal deposition and assembly of a distinct, transient intraluminal matrix. Drosophila γCOP colocalizes with cis-Golgi markers and in γCOP mutant embryos the ER and Golgi structures are severely disrupted. Analysis of γCOP and Sar1 double mutants suggests that bidirectional ER-Golgi traffic maintains the ER and Golgi compartments and is required for secretion and assembly of luminal matrixes during tube expansion.

Conclusions/Significance Our results demonstrate the function of COPI components in organ morphogenesis and highlight the common role of apical secretion and assembly of transient organotypic matrices in tube expansion. Intraluminal matrices have been detected in the notochord of ascidians and zebrafish COPI mutants show defects in notochord expansion. Thus, the programmed deposition and growth of distinct luminal molds may provide distending forces during tube expansion in diverse organs.

National Category
Developmental Biology
Research subject
Developmental Biology
Identifiers
urn:nbn:se:su:diva-32569 (URN)10.1371/journal.pone.0001964 (DOI)000260795500033 ()
Available from: 2009-12-15 Created: 2009-12-14 Last updated: 2017-12-12Bibliographically approved
3. Epithelial septate junction assembly relies on melanotransferrin iron binding and endocytosis in Drosophila
Open this publication in new window or tab >>Epithelial septate junction assembly relies on melanotransferrin iron binding and endocytosis in Drosophila
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2010 (English)In: Nature Cell Biology, ISSN 1465-7392, E-ISSN 1476-4679, Vol. 12, no 11, 1071-1077 p.Article in journal (Refereed) Published
Abstract [en]

Iron is an essential element in many biological processes. In vertebrates, serum transferrin is the major supplier of iron to tissues, but the function of additional transferrin-like proteins remains poorly understood. Melanotransferrin (MTf) is a phylogenetically conserved, iron-binding epithelial protein. Elevated MTf levels have been implicated in melanoma pathogenesis. Here, we present a functional analysis of MTf in Drosophila melanogaster. Similarly to its human homologue, Drosophila MTf is a lipid-modified, iron-binding protein attached to epithelial cell membranes, and is a component of the septate junctions that form the paracellular permeability barrier in epithelial tissues. We demonstrate that septate junction assembly during epithelial maturation relies on endocytosis and apicolateral recycling of iron-bound MTf. Mouse MTf complements the defects of Drosophila MTf mutants. Drosophila provides the first genetic model for the functional dissection of MTf in epithelial junction assembly and morphogenesis.

National Category
Developmental Biology
Research subject
Developmental Biology
Identifiers
urn:nbn:se:su:diva-45025 (URN)10.1038/ncb2111 (DOI)000283711500010 ()20935638 (PubMedID)
Available from: 2010-11-09 Created: 2010-11-09 Last updated: 2017-12-12Bibliographically approved
4. Control of tube diameter expansion by secreted chitin-binding proteins
Open this publication in new window or tab >>Control of tube diameter expansion by secreted chitin-binding proteins
(English)Manuscript (preprint) (Other academic)
Abstract [en]

The size and shape of epithelial tubes determine the transporting capacities of tubular organs. Here, we analyze two genes involved in airway tube size regulation in Drosophila. Obst-A and gasp encode secreted proteins with chitin binding domains that are conserved among insect species. mRNA in situ hybridizations show that both genes are strongly expressed during airway tube expansion. Gasp protein is secreted into the airway tubes and colocalizes with a chitin binding probe and other chitin binding proteins. Analysis of obst-A and gasp single mutants and obst-A; gasp double mutant shows that both genes are required for larval elongation and airway tube dilation. The assembly of the apical chitinous matrix of the airway tubes is defective in gasp and Obst-A mutants. The defects become exaggerated in double mutants indicating that the genes have partially redundant functions in chitin structure modification. The phenotypes in luminal chitin assembly in the airway tubes are accompanied with a corresponding reduction of tube diameter in the mutants. Conversely, overexpression of Obst-A or Gasp in the airways expands the tube circumference.  Our results indicate that the level of distinct matrix binding proteins in the tubes determines the extent of diametric growth. We propose that Obst-A and Gasp organize the assembly of the luminal matrix and thereby provide distending forces that stretch the apical cell membranes to expand tube diameter accordingly.

National Category
Developmental Biology
Research subject
Developmental Biology
Identifiers
urn:nbn:se:su:diva-62417 (URN)
Available from: 2011-09-19 Created: 2011-09-19 Last updated: 2011-09-29Bibliographically approved

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