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Gängel, Konstantin
Alternative names
Publications (9 of 9) Show all publications
Castro, M., Laviña, B., Ando, K., Alvarez-Aznar, A., Abu Taha, A., Brakebusch, C., . . . Gängel, K. (2019). CDC42 deletion elicits cerebral vascular malformations via increased MEKK3-dependent KLF4 expression. Circulation Research, 124(8), 1240-1252
Open this publication in new window or tab >>CDC42 deletion elicits cerebral vascular malformations via increased MEKK3-dependent KLF4 expression
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2019 (English)In: Circulation Research, ISSN 0009-7330, E-ISSN 1524-4571, Vol. 124, no 8, p. 1240-1252Article in journal (Refereed) Published
Abstract [en]

Rationale: Aberrant formation of blood vessels precedes a broad spectrum of vascular complications; however, the cellular and molecular events governing vascular malformations are not yet fully understood. Objective: Here, we investigated the role of CDC42 (cell division cycle 42) during vascular morphogenesis and its relative importance for the development of cerebrovascular malformations. Methods and Results: To avoid secondary systemic effects often associated with embryonic gene deletion, we generated an endothelial-specific and inducible knockout approach to study postnatal vascularization of the mouse brain. Postnatal endothelial-specific deletion of Cdc42 elicits cerebrovascular malformations reminiscent of cerebral cavernous malformations (CCMs). At the cellular level, loss of CDC42 function in brain endothelial cells (ECs) impairs their sprouting, branching morphogenesis, axial polarity, and normal dispersion within the brain tissue. Disruption of CDC42 does not alter EC proliferation, but malformations occur where EC proliferation is the most pronounced during brain development-the postnatal cerebellum-indicating that a high, naturally occurring EC proliferation provides a permissive state for the appearance of these malformations. Mechanistically, CDC42 depletion in ECs elicited increased MEKK3 (mitogen-activated protein kinase kinase kinase 3)-MEK5 (mitogen-activated protein kinase kinase 5)-ERK5 (extracellular signal-regulated kinase 5) signaling and consequent detrimental overexpression of KLF (Kruppel-like factor) 2 and KLF4, recapitulating the hallmark mechanism for CCM pathogenesis. Through genetic approaches, we demonstrate that the coinactivation of Klf4 reduces the severity of vascular malformations in Cdc42 mutant mice. Moreover, we show that CDC42 interacts with CCMs and that CCM3 promotes CDC42 activity in ECs. Conclusions: We show that endothelial-specific deletion of Cdc42 elicits CCM-like cerebrovascular malformations and that CDC42 is engaged in the CCM signaling network to restrain the MEKK3-MEK5-ERK5-KLF2/4 pathway.

Keywords
Angiogenesis, vascular morphogenesis, cerebrovascular malformation, endothelial cells, CDC42, MEKK3 signaling, KLF2/4
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-347776 (URN)10.1161/CIRCRESAHA.118.314300 (DOI)000469343500021 ()30732528 (PubMedID)
Funder
Swedish Cancer Society, CAN2015/771Swedish Research Council, VR2015-00550EU, European Research Council, 2011-294556 742922Knut and Alice Wallenberg Foundation, 2012.0272EU, FP7, Seventh Framework Programme, 317250Wenner-Gren FoundationsDanish National Research Foundation
Note

List of authors in thesis manuscript: Castro, M, Laviña, B, Ando, K, Álvarez-Aznar, A, Brakebusch, C, Dejana, E, Betsholtz, C, Gängel, K

Available from: 2018-04-06 Created: 2018-04-06 Last updated: 2019-06-25Bibliographically approved
Thuveson, M., Gängel, K., Collu, G. M., Chin, M.-l., Singh, J. & Mlodzik, M. (2019). Integrins are required for synchronous ommatidial rotation in the Drosophila eye linking planar cell polarity signalling to the extracellular matrix. Open Biology, 9(8), Article ID 190148.
Open this publication in new window or tab >>Integrins are required for synchronous ommatidial rotation in the Drosophila eye linking planar cell polarity signalling to the extracellular matrix
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2019 (English)In: Open Biology, ISSN 2046-2441, E-ISSN 2046-2441, Vol. 9, no 8, article id 190148Article in journal (Refereed) Published
Abstract [en]

Integrins mediate the anchorage between cells and their environment, the extracellular matrix (ECM), and form transmembrane links between the ECM and the cytoskeleton, a conserved feature throughout development and morphogenesis of epithelial organs. Here, we demonstrate that integrins and components of the ECM are required during the planar cell polarity (PCP) signalling-regulated cell movement of ommatidial rotation in the Drosophila eye. The loss-of-function mutations of integrins or ECM components cause defects in rotation, with mutant clusters rotating asynchronously compared to wild-type clusters. Initially, mutant clusters tend to rotate faster, and at later stages they fail to be synchronous with their neighbours, leading to aberrant rotation angles and resulting in a disorganized ommatidial arrangement in adult eyes. We further demonstrate that integrin localization changes dynamically during the rotation process. Our data suggest that core Frizzled/PCP factors, acting through RhoA and Rho kinase, regulate the function/activity of integrins and that integrins thus contribute to the complex interaction network of PCP signalling, cell adhesion and cytoskeletal elements required for a precise and synchronous 90 degrees rotation movement.

Place, publisher, year, edition, pages
ROYAL SOC, 2019
Keywords
planar cell polarity, Drosophila eye, ommatidial rotation, integrins, extracellular matrix
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-394163 (URN)10.1098/rsob.190148 (DOI)000483917300006 ()31409231 (PubMedID)
Available from: 2019-10-04 Created: 2019-10-04 Last updated: 2019-10-04Bibliographically approved
Alvarez, A., Martinez-Corral, I., Daubel, N., Betsholtz, C., Mäkinen, T. & Gängel, K. (2019). Tamoxifen-independent recombination of reporter genes limits lineage tracing and mosaic analysis using CreER(T2) lines. Transgenic research
Open this publication in new window or tab >>Tamoxifen-independent recombination of reporter genes limits lineage tracing and mosaic analysis using CreER(T2) lines
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2019 (English)In: Transgenic research, ISSN 0962-8819, E-ISSN 1573-9368Article in journal (Refereed) Epub ahead of print
Abstract [en]

The CreER(T2)/loxP system is widely used to induce conditional gene deletion in mice. One of the main advantages of the system is that Cre-mediated recombination can be controlled in time through Tamoxifen administration. This has allowed researchers to study the function of embryonic lethal genes at later developmental timepoints. In addition, CreER(T2) mouse lines are commonly used in combination with reporter genes for lineage tracing and mosaic analysis. In order for these experiments to be reliable, it is crucial that the cell labeling approach only marks the desired cell population and their progeny, as unfaithful expression of reporter genes in other cell types or even unintended labeling of the correct cell population at an undesired time point could lead to wrong conclusions. Here we report that all CreER(T2) mouse lines that we have studied exhibit a certain degree of Tamoxifen-independent, basal, Cre activity. Using Ai14 and Ai3, two commonly used fluorescent reporter genes, we show that those basal Cre activity levels are sufficient to label a significant amount of cells in a variety of tissues during embryogenesis, postnatal development and adulthood. This unintended labelling of cells imposes a serious problem for lineage tracing and mosaic analysis experiments. Importantly, however, we find that reporter constructs differ greatly in their susceptibility to basal CreER(T2) activity. While Ai14 and Ai3 easily recombine under basal CreER(T2) activity levels, mTmG and R26R-EYFP rarely become activated under these conditions and are therefore better suited for cell tracking experiments.

Keywords
CreER(T2), Cre, loxP system, Lineage tracing, Mosaic analysis, Tamoxifen-independent recombination, Reporter-gene
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-397671 (URN)10.1007/s11248-019-00177-8 (DOI)000494238200001 ()31641921 (PubMedID)
Funder
Swedish Cancer Society, CAN2015/771Swedish Cancer Society, CAN 2016/535Swedish Research Council, VR2015-00550Swedish Research Council, 542-2014-3535EU, European Research Council, 2011-294556EU, European Research Council, ERC-2014-CoG-646849Knut and Alice Wallenberg Foundation, 2012.0272Knut and Alice Wallenberg Foundation, 2015.0030
Available from: 2019-11-28 Created: 2019-11-28 Last updated: 2019-11-28Bibliographically approved
Laviña, B., Castro, M., Niaudet, C., Cruys, B., Álvarez-Aznar, A., Carmeliet, P., . . . Gängel, K. (2018). Defective endothelial cell migration in the absence of Cdc42 leads to capillary-venous malformations. Development, 145(13), Article ID UNSP dev161182.
Open this publication in new window or tab >>Defective endothelial cell migration in the absence of Cdc42 leads to capillary-venous malformations
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2018 (English)In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 145, no 13, article id UNSP dev161182Article in journal (Refereed) Published
Abstract [en]

Formation and homeostasis of the vascular system requires several coordinated cellular functions, but their precise interplay during development and their relative importance for vascular pathologies remain poorly understood. Here, we investigated the endothelial functions regulated by Cdc42 and their in vivo relevance during angiogenic sprouting and vascular morphogenesis in the postnatal mouse retina. We found that Cdc42 is required for endothelial tip cell selection, directed cell migration and filopodia formation, but dispensable for cell proliferation or apoptosis. Although the loss of Cdc42 seems generally compatible with apical-basal polarization and lumen formation in retinal blood vessels, it leads to defective endothelial axial polarization and to the formation of severe vascular malformations in capillaries and veins. Tracking of Cdc42-depleted endothelial cells in mosaic retinas suggests that these capillary-venous malformations arise as a consequence of defective cell migration, when endothelial cells that proliferate at normal rates are unable to re-distribute within the vascular network.

Keywords
Vascular malformations, Cdc42, Cell migration, Endothelial axial polarity, Angiogenesis, Proliferation
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-361537 (URN)10.1242/dev.161182 (DOI)000439224400008 ()29853619 (PubMedID)
Funder
Swedish Research Council, VR2015-00550EU, European Research Council, 2011-294556EU, European Research Council, EU-ERC269073Knut and Alice Wallenberg Foundation, 2012.0272EU, FP7, Seventh Framework Programme, 317250Swedish Cancer Society, CAN2015/771The Wenner-Gren Foundation
Available from: 2018-10-01 Created: 2018-10-01 Last updated: 2018-10-01Bibliographically approved
Collu, G. M., Jenny, A., Gängel, K., Mirkovic, I., Chin, M., Weber, U., . . . Mlodzik, M. (2018). Prickle is phosphorylated by Nemo and targeted for degradation to maintain Prickle/Spiny-legs isoform balance during planar cell polarity establishment. PLoS Genetics, 14(5), Article ID e1007391.
Open this publication in new window or tab >>Prickle is phosphorylated by Nemo and targeted for degradation to maintain Prickle/Spiny-legs isoform balance during planar cell polarity establishment
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2018 (English)In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 14, no 5, article id e1007391Article in journal (Refereed) Published
Abstract [en]

Planar cell polarity (PCP) instructs tissue patterning in a wide range of organisms from fruit flies to humans. PCP signaling coordinates cell behavior across tissues and is integrated by cells to couple cell fate identity with position in a developing tissue. In the fly eye, PCP signaling is required for the specification of R3 and R4 photoreceptors based upon their positioning relative to the dorso-ventral axis. The 'core' PCP pathway involves the asymmetric localization of two distinct membrane-bound complexes, one containing Frizzled (Fz, required in R3) and the other Van Gogh (Vang, required in R4). Inhibitory interactions between the cytosolic components of each complex reinforce asymmetric localization. Prickle (Pk) and Spiny-legs (Pk-Sple) are two antagonistic isoforms of the prickle (pk) gene and are cytoplasmic components of the Vang complex. The balance between their levels is critical for tissue patterning, with Pk-Sple being the major functional isoform in the eye. Here we uncover a post-translational role for Nemo kinase in limiting the amount of the minor isoform Pk. We identified Pk as a Nemo substrate in a genome-wide in vitro band-shift screen. In vivo, nemo genetically interacts with pk(pk) but not pk(sple) and enhances PCP defects in the eye and leg. Nemo phosphorylation limits Pk levels and is required specifically in the R4 photoreceptor like the major isoform, Pk-Sple. Genetic interaction and biochemical data suggest that Nemo phosphorylation of Pk leads to its proteasomal degradation via the Cullin1/SkpA/Slmb complex. dTAK and Homeodomain interacting protein kinase (Hipk) may also act together with Nemo to target Pk for degradation, consistent with similar observations in mammalian studies. Our results therefore demonstrate a mechanism to maintain low levels of the minor Pk isoform, allowing PCP complexes to form correctly and specify cell fate.

Place, publisher, year, edition, pages
PUBLIC LIBRARY SCIENCE, 2018
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-364481 (URN)10.1371/journal.pgen.1007391 (DOI)000434016500035 ()29758044 (PubMedID)
Available from: 2018-10-30 Created: 2018-10-30 Last updated: 2018-10-30Bibliographically approved
Niaudet, C., Hofmann, J. J., Mae, M. A., Jung, B., Gängel, K., Vanlandewijck, M., . . . Betsholtz, C. (2015). Gpr116 Receptor Regulates Distinctive Functions in Pneumocytes and Vascular Endothelium. PLoS ONE, 10(9), Article ID e0137949.
Open this publication in new window or tab >>Gpr116 Receptor Regulates Distinctive Functions in Pneumocytes and Vascular Endothelium
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2015 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 9, article id e0137949Article in journal (Refereed) Published
Abstract [en]

Despite its known expression in both the vascular endothelium and the lung epithelium, until recently the physiological role of the adhesion receptor Gpr116/ADGRF5 has remained elusive. We generated a new mouse model of constitutive Gpr116 inactivation, with a large genetic deletion encompassing exon 4 to exon 21 of the Gpr116 gene. This model allowed us to confirm recent results defining Gpr116 as necessary regulator of surfactant homeostasis. The loss of Gpr116 provokes an early accumulation of surfactant in the lungs, followed by a massive infiltration of macrophages, and eventually progresses into an emphysemalike pathology. Further analysis of this knockout model revealed cerebral vascular leakage, beginning at around 1.5 months of age. Additionally, endothelial-specific deletion of Gpr116 resulted in a significant increase of the brain vascular leakage. Mice devoid of Gpr116 developed an anatomically normal and largely functional vascular network, surprisingly exhibited an attenuated pathological retinal vascular response in a model of oxygen-induced retinopathy. These data suggest that Gpr116 modulates endothelial properties, a previously unappreciated function despite the pan-vascular expression of this receptor. Our results support the key pulmonary function of Gpr116 and describe a new role in the central nervous system vasculature.

National Category
Immunology in the medical area Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-265915 (URN)10.1371/journal.pone.0137949 (DOI)000361792100023 ()26394398 (PubMedID)
Funder
EU, European Research Council, 294556EU, European Research Council, ITN-2012-317250-VESSELSwedish Cancer SocietySwedish Research CouncilKnut and Alice Wallenberg Foundation
Available from: 2015-11-04 Created: 2015-11-04 Last updated: 2018-04-07
Lavina, B. & Gängel, K. (2015). New imaging methods and tools to study vascular biology. Current opinion in hematology, 22(3), 258-266
Open this publication in new window or tab >>New imaging methods and tools to study vascular biology
2015 (English)In: Current opinion in hematology, ISSN 1065-6251, E-ISSN 1531-7048, Vol. 22, no 3, p. 258-266Article, review/survey (Refereed) Published
Abstract [en]

Purpose of review Throughout history, development of novel microscopy techniques has been of fundamental importance to advance the vascular biology field. This review offers a concise summary of the most recently developed imaging techniques and discusses how they can be applied to vascular biology. In addition, we reflect upon the most important fluorescent reporters for vascular research that are currently available. Recent findings Recent advances in light sheet-based imaging techniques now offer the ability to live image the vascular system in whole organs or even in whole animals during development and in pathological conditions with a satisfactory spatial and temporal resolution. Conversely, super resolution microscopy now allows studying cellular processes at a near-molecular resolution. Summary Major recent improvements in a number of imaging techniques now allow study of vascular biology in ways that could not be considered previously. Researchers now have well-developed tools to specifically examine the dynamic nature of vascular development during angiogenic sprouting, remodeling and regression as well as the vascular responses in disease situations in vivo. In addition, open questions in endothelial and lymphatic cell biology that require subcellular resolution such as actin dynamics, junctional complex formation and stability, vascular permeability and receptor trafficking can now be approached with high resolution.

Keywords
in-vivo imaging, light sheet microscopy, super resolution microscopy, tissue clearing techniques, vascular biology
National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-255014 (URN)10.1097/MOH.0000000000000141 (DOI)000352793900010 ()25767958 (PubMedID)
Available from: 2015-06-15 Created: 2015-06-12 Last updated: 2017-12-04Bibliographically approved
Gängel, K. & Betsholtz, C. (2013). Endocytosis regulates VEGF signalling during angiogenesis. Nature Cell Biology, 15(3), 233-235
Open this publication in new window or tab >>Endocytosis regulates VEGF signalling during angiogenesis
2013 (English)In: Nature Cell Biology, ISSN 1465-7392, E-ISSN 1476-4679, Vol. 15, no 3, p. 233-235Article in journal, Editorial material (Other academic) Published
Abstract [en]

Endocytosis has proved to be a versatile mechanism regulating diverse cellular processes, ranging from nutrient uptake to intracellular signal transduction. New work reinforces the importance of endocytosis for VEGF receptor signalling and angiogenesis in the developing eye, and describes a mechanism for its differential regulation in angiogenic versus quiescent endothelial cells.

National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-198102 (URN)10.1038/ncb2705 (DOI)000315844900002 ()
Available from: 2013-04-09 Created: 2013-04-09 Last updated: 2017-12-06Bibliographically approved
Laviña, B., Castro, M., Niaudet, C., Bert, C., Peter, C., Bentley, K., . . . Gängel, K.Defective endothelial cell migration in the absence of Cdc42 leads to capillary-venous malformations: Cdc42 and vascular malformations.
Open this publication in new window or tab >>Defective endothelial cell migration in the absence of Cdc42 leads to capillary-venous malformations: Cdc42 and vascular malformations
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(English)Manuscript (preprint) (Other academic)
Keywords
Vascular malformations, Cdc42, cell migration, planar-cell-polarity, angiogenesis, proliferation
National Category
Cell Biology
Identifiers
urn:nbn:se:uu:diva-347774 (URN)
Available from: 2018-04-06 Created: 2018-04-06 Last updated: 2018-10-01Bibliographically approved
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