Staccato/Unc-13-4 controls secretory lysosome-mediated lumen fusion during epithelial tube anastomosis

2016 ◽  
Vol 18 (7) ◽  
pp. 727-739 ◽  
Author(s):  
Sara Caviglia ◽  
Marko Brankatschk ◽  
Elisabeth J. Fischer ◽  
Suzanne Eaton ◽  
Stefan Luschnig
Keyword(s):  
Secretory Lysosome ◽  
Epithelial Tube

scholarly journals Following the ‘tracks’: Tramtrack69 regulates epithelial tube expansion in the Drosophila ovary through Paxillin, Dynamin, and the homeobox protein Mirror

2013 ◽  
Vol 378 (2) ◽  
pp. 154-169 ◽  
Author(s):  
Nathaniel C. Peters ◽  
Nathaniel H. Thayer ◽  
Scott A. Kerr ◽  
Martin Tompa ◽  
Celeste A. Berg
Keyword(s):  
Epithelial Tube ◽  
Homeobox Protein ◽  
Drosophila Ovary ◽  
Tube Expansion

scholarly journals RYK-mediated filopodial pathfinding facilitates midgut elongation

Development ◽  
2020 ◽  
Vol 147 (20) ◽  
pp. dev195388
Author(s):  
Sha Wang ◽  
James P. Roy ◽  
Abigail J. Tomlinson ◽  
Ellen B. Wang ◽  
Yu-Hwai Tsai ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Navigation System ◽  
De Novo ◽  
Basal Surface ◽  
Daughter Cells ◽  
Guidance Cue ◽  
Epithelial Tube ◽  
Pseudostratified Epithelium ◽  
Rapid Elongation ◽  
Active Proliferation

ABSTRACTBetween embryonic days 10.5 and 14.5, active proliferation drives rapid elongation of the murine midgut epithelial tube. Within this pseudostratified epithelium, nuclei synthesize DNA near the basal surface and move apically to divide. After mitosis, the majority of daughter cells extend a long, basally oriented filopodial protrusion, building a de novo path along which their nuclei can return to the basal side. WNT5A, which is secreted by surrounding mesenchymal cells, acts as a guidance cue to orchestrate this epithelial pathfinding behavior, but how this signal is received by epithelial cells is unknown. Here, we have investigated two known WNT5A receptors: ROR2 and RYK. We found that epithelial ROR2 is dispensable for midgut elongation. However, loss of Ryk phenocopies the Wnt5a−/− phenotype, perturbing post-mitotic pathfinding and leading to apoptosis. These studies reveal that the ligand-receptor pair WNT5A-RYK acts as a navigation system to instruct filopodial pathfinding, a process that is crucial for continuous cell cycling to fuel rapid midgut elongation.

The munc13-4–rab27 complex is specifically required for tethering secretory lysosomes at the plasma membrane

Blood ◽  
2011 ◽  
Vol 118 (6) ◽  
pp. 1570-1578 ◽  
Author(s):  
Edo D. Elstak ◽  
Maaike Neeft ◽  
Nadine T. Nehme ◽  
Jarno Voortman ◽  
Marc Cheung ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Immune Cells ◽  
Total Internal Reflection ◽  
Target Cells ◽  
Binding Motif ◽  
Microscopy Imaging ◽  
Secretory Lysosome ◽  
Mast Cell Line ◽  
Type 3 ◽  
Secretory Lysosomes

Abstract Cytotoxic T lymphocytes (CTLs) kill target cells through the polarized release of lytic molecules from secretory lysosomes. Loss of munc13-4 function inhibits this process and causes familial hemophagocytic lymphohistiocytosis type 3 (FHL3). munc13-4 binds rab27a, but the necessity of the complex remains enigmatic, because studies in knockout models suggest separate functions. In the present study, we describe a noncanonical rab27a-binding motif in the N-terminus of munc13-4. Point mutants in this sequence have severely impaired rab27a binding, allowing dissection of rab27a requirements in munc13-4 function. The munc13-4–rab27a complex is not needed for secretory lysosome maturation, as shown by complementation in CTLs from FHL3 patients and in a mast cell line silenced for munc13-4. In contrast, fusion of secretory lysosomes with, and content release at the plasma membrane during degranulation, strictly required the munc13-4–rab27a complex. Total internal reflection fluorescence microscopy imaging revealed that the complex corrals motile secretory lysosomes beneath the plasma membrane during degranulation and controls their docking. The propensity to stall motility of secretory lysosomes is lost in cells expressing munc13-4 point mutants that do not bind rab27. In summary, these results uncovered a mechanism for tethering secretory lysosomes to the plasma membrane that is essential for degranulation in immune cells.

scholarly journals Munc13-4 Is an Effector of Rab27a and Controls Secretion of Lysosomes in Hematopoietic Cells

2005 ◽  
Vol 16 (2) ◽  
pp. 731-741 ◽  
Author(s):  
Maaike Neeft ◽  
Marnix Wieffer ◽  
Arjan S. de Jong ◽  
Gabriela Negroiu ◽  
Corina H.G. Metz ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Mast Cells ◽  
Genetic Disorder ◽  
Hematopoietic Cells ◽  
Lytic Granules ◽  
Secretory Lysosome ◽  
Griscelli Syndrome ◽  
Life Threatening ◽  
Lytic Granule ◽  
Secretory Lysosomes

Griscelli syndrome type 2 (GS2) is a genetic disorder in which patients exhibit life-threatening defects of cytotoxic T lymphocytes (CTLs) whose lytic granules fail to dock on the plasma membrane and therefore do not release their contents. The disease is caused by the absence of functional rab27a, but how rab27a controls secretion of lytic granule contents remains elusive. Mutations in Munc13-4 cause familial hemophagocytic lymphohistiocytosis subtype 3 (FHL3), a disease phenotypically related to GS2. We show that Munc13-4 is a direct partner of rab27a. The two proteins are highly expressed in CTLs and mast cells where they colocalize on secretory lysosomes. The region comprising the Munc13 homology domains is essential for the localization of Munc13-4 to secretory lysosomes. The GS2 mutant rab27aW73G strongly reduced binding to Munc13-4, whereas the FHL3 mutant Munc13-4Δ608-611 failed to bind rab27a. Overexpression of Munc13-4 enhanced degranulation of secretory lysosomes in mast cells, showing that it has a positive regulatory role in secretory lysosome fusion. We suggest that the secretion defects seen in GS2 and FHL3 have a common origin, and we propose that the rab27a/Munc13-4 complex is an essential regulator of secretory granule fusion with the plasma membrane in hematopoietic cells. Mutations in either of the two genes prevent formation of this complex and abolish secretion.

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