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Majumdar, Arindam
Publications (7 of 7) Show all publications
Abu-Siniyeh, A., Owen, D. M., Benzing, C., Rinkwitz, S., Becker, T. S., Majumdar, A. & Gaus, K. (2016). The aPKC/Par3/Par6 Polarity Complex and Membrane Order Are Functionally Interdependent in Epithelia During Vertebrate Organogenesis. Traffic: the International Journal of Intracellular Transport, 17(1), 66-79
Open this publication in new window or tab >>The aPKC/Par3/Par6 Polarity Complex and Membrane Order Are Functionally Interdependent in Epithelia During Vertebrate Organogenesis
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2016 (English)In: Traffic: the International Journal of Intracellular Transport, ISSN 1398-9219, E-ISSN 1600-0854, Vol. 17, no 1, p. 66-79Article in journal (Refereed) Published
Abstract [en]

The differential distribution of lipids between apical and basolateral membranes is necessary for many epithelial cell functions, but how this characteristic membrane organization is integrated within the polarity network during ductal organ development is poorly understood. Here we quantified membrane order in the gut, kidney and liver ductal epithelia in zebrafish larvae at 3-11 days post fertilization (dpf) with Laurdan 2-photon microscopy. We then applied a combination of Laurdan imaging, antisense knock-down and analysis of polarity markers to understand the relationship between membrane order and apical-basal polarity. We found a reciprocal relationship between membrane order and the cell polarity network. Reducing membrane condensation by exogenously added oxysterol or depletion of cholesterol reduced apical targeting of the polarity protein, aPKC. Conversely, using morpholino knock down in zebrafish, we found that membrane order was dependent upon the Crb3 and Par3 polarity protein expression in ductal epithelia. Hence our data suggest that the biophysical property of membrane lipid packing is a regulatory element in apical basal polarity.

Keywords
apical and basolateral membranes, epithelial cell, lipid phases, membrane organization, polarity proteins, zebrafish larvae
National Category
Cell Biology
Identifiers
urn:nbn:se:uu:diva-274433 (URN)10.1111/tra.12339 (DOI)000366975200005 ()26456025 (PubMedID)
Funder
Swedish Research Council
Available from: 2016-01-21 Created: 2016-01-21 Last updated: 2017-11-30Bibliographically approved
Ebarasi, L., Ashraf, S., Bierzynska, A., Gee, H. Y., McCarthy, H. J., Lovric, S., . . . Majumdar, A. (2015). Defects of CRB2 Cause Steroid-Resistant Nephrotic Syndrome. American Journal of Human Genetics, 96(1), 153-161
Open this publication in new window or tab >>Defects of CRB2 Cause Steroid-Resistant Nephrotic Syndrome
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2015 (English)In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 96, no 1, p. 153-161Article in journal (Refereed) Published
Abstract [en]

Nephrotic syndrome (NS), the association of gross proteinuria, hypoalbuminaemia, edema, and hyperlipidemia, can be clinically divided into steroid-sensitive (SSNS) and steroid-resistant (SRNS) forms. SRNS regularly progresses to end-stage renal failure. By homozygosity mapping and whole exome sequencing, we here identify recessive mutations in Crumbs homolog 2 (CRB2) in four different families affected by SRNS. Previously, we established a requirement for zebrafish crb2b, a conserved regulator of epithelial polarity, in podocyte morphogenesis. By characterization of a loss-of-function mutation in zebrafish crb2b, we now show that zebrafish crb2b is required for podocyte foot process arborization, slit diaphragm formation, and proper nephrin trafficking. Furthermore, by complementation experiments in zebrafish, we demonstrate that CRB2 mutations result in loss of function and therefore constitute causative mutations leading to NS in humans. These results implicate defects in podocyte apico-basal polarity in the pathogenesis of NS.

National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-247168 (URN)10.1016/j.ajhg.2014.11.014 (DOI)000347707800012 ()25557779 (PubMedID)
Available from: 2015-03-16 Created: 2015-03-13 Last updated: 2018-01-11Bibliographically approved
Hultin, S., Zheng, Y., Mojallal, M., Vertuani, S., Gentili, C., Balland, M., . . . Holmgren, L. (2014). AmotL2 links VE-cadherin to contractile actin fibres necessary for aortic lumen expansion. Nature Communications, 5, Article ID 3743.
Open this publication in new window or tab >>AmotL2 links VE-cadherin to contractile actin fibres necessary for aortic lumen expansion
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2014 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 5, article id 3743Article in journal (Refereed) Published
Abstract [en]

The assembly of individual endothelial cells into multicellular tubes is a complex morphogenetic event in vascular development. Extracellular matrix cues and cell-cell junctional communication are fundamental to tube formation. Together they determine the shape of endothelial cells and the tubular structures that they ultimately form. Little is known regarding how mechanical signals are transmitted between cells to control cell shape changes during morphogenesis. Here we provide evidence that the scaffold protein amotL2 is needed for aortic vessel lumen expansion. Using gene inactivation strategies in zebrafish, mouse and endothelial cell culture systems, we show that amotL2 associates to the VE-cadherin adhesion complex where it couples adherens junctions to contractile actin fibres. Inactivation of amotL2 dissociates VE-cadherin from cytoskeletal tensile forces that affect endothelial cell shape. We propose that the VE-cadherin/amotL2 complex is responsible for transmitting mechanical force between endothelial cells for the coordination of cellular morphogenesis consistent with aortic lumen expansion and function.

National Category
Basic Medicine
Identifiers
urn:nbn:se:uu:diva-321319 (URN)10.1038/ncomms4743 (DOI)24806444 (PubMedID)
Available from: 2017-05-03 Created: 2017-05-03 Last updated: 2018-01-13Bibliographically approved
Ebarasi, L., Gaengel, K., Majumdar, A. & Betsholtz, C. (2013). Evidence for the presence of pericytes in the zebrafish. Paper presented at NAVBO Workshops in Vascular Biology; 14-18 2012; Pacific Grove, CA, USA. Angiogenesis, 16(1), 273-273
Open this publication in new window or tab >>Evidence for the presence of pericytes in the zebrafish
2013 (English)In: Angiogenesis, ISSN 0969-6970, E-ISSN 1573-7209, Vol. 16, no 1, p. 273-273Article in journal, Meeting abstract (Other academic) Published
National Category
Medical and Health Sciences Natural Sciences
Identifiers
urn:nbn:se:uu:diva-192671 (URN)000312658800128 ()
Conference
NAVBO Workshops in Vascular Biology; 14-18 2012; Pacific Grove, CA, USA
Available from: 2013-01-24 Created: 2013-01-24 Last updated: 2017-12-06Bibliographically approved
Gaengel, K., Niaudet, C., Hagikura, K., Siemsen, L. B., Muhl, L., Hofmann, J. J., . . . Betsholtz, C. (2013). The sphingosine-1-phosphate receptor S1PR1 restricts sprouting angiogenesis by regulating the interplay between VE-cadherin and VEGFR2. Paper presented at NAVBO Workshops in Vascular Biology; 14-18 Oct 2012; Pacific Grove, CA, USA. Angiogenesis, 16(1), 246-247
Open this publication in new window or tab >>The sphingosine-1-phosphate receptor S1PR1 restricts sprouting angiogenesis by regulating the interplay between VE-cadherin and VEGFR2
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2013 (English)In: Angiogenesis, ISSN 0969-6970, E-ISSN 1573-7209, Vol. 16, no 1, p. 246-247Article in journal, Meeting abstract (Other academic) Published
National Category
Medical and Health Sciences Natural Sciences
Identifiers
urn:nbn:se:uu:diva-192670 (URN)000312658800027 ()
Conference
NAVBO Workshops in Vascular Biology; 14-18 Oct 2012; Pacific Grove, CA, USA
Available from: 2013-01-24 Created: 2013-01-24 Last updated: 2017-12-06Bibliographically approved
Hayashi, M., Majumdar, A., Li, X., Adler, J., Sun, Z., Vertuani, S., . . . Claesson-Welsh, L. (2013). VE-PTP regulates VEGFR2 activity in stalk cells to establish endothelial cell polarity and lumen formation. Nature Communications, 4, 1672
Open this publication in new window or tab >>VE-PTP regulates VEGFR2 activity in stalk cells to establish endothelial cell polarity and lumen formation
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2013 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 4, p. 1672-Article in journal (Refereed) Published
Abstract [en]

Vascular endothelial growth factor (VEGF) guides the path of new vessel sprouts by inducing VEGF receptor-2 activity in the sprout tip. In the stalk cells of the sprout, VEGF receptor-2 activity is downregulated. Here, we show that VEGF receptor-2 in stalk cells is dephosphorylated by the endothelium-specific vascular endothelial-phosphotyrosine phosphatase (VE-PTP). VE-PTP acts on VEGF receptor-2 located in endothelial junctions indirectly, via the Angiopoietin-1 receptor Tie2. VE-PTP inactivation in mouse embryoid bodies leads to excess VEGF receptor-2 activity in stalk cells, increased tyrosine phosphorylation of VE-cadherin and loss of cell polarity and lumen formation. Vessels in ve-ptp(-/-) teratomas also show increased VEGF receptor-2 activity and loss of endothelial polarization. Moreover, the zebrafish VE-PTP orthologue ptp-rb is essential for polarization and lumen formation in intersomitic vessels. We conclude that the role of Tie2 in maintenance of vascular quiescence involves VE-PTP-dependent dephosphorylation of VEGF receptor-2, and that VEGF receptor-2 activity regulates VE-cadherin tyrosine phosphorylation, endothelial cell polarity and lumen formation.

National Category
Natural Sciences Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-202980 (URN)10.1038/ncomms2683 (DOI)000318872100029 ()
Available from: 2013-07-01 Created: 2013-07-01 Last updated: 2017-12-06Bibliographically approved
Gaengel, K., Niaudet, C., Hagikura, K., Siemsen, B. L., Muhl, L., Hofmann, J. J., . . . Betsholtz, C. (2012). The Sphingosine-1-Phosphate Receptor S1PR1 Restricts Sprouting Angiogenesis by Regulating the Interplay between VE-Cadherin and VEGFR2. Developmental Cell, 23(3), 587-599
Open this publication in new window or tab >>The Sphingosine-1-Phosphate Receptor S1PR1 Restricts Sprouting Angiogenesis by Regulating the Interplay between VE-Cadherin and VEGFR2
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2012 (English)In: Developmental Cell, ISSN 1534-5807, E-ISSN 1878-1551, Vol. 23, no 3, p. 587-599Article in journal (Refereed) Published
Abstract [en]

Angiogenesis, the process by which new blood vessels arise from preexisting ones, is critical for embryonic development and is an integral part of many disease processes. Recent studies have provided detailed information on how angiogenic sprouts initiate, elongate, and branch, but less is known about how these processes cease. Here, we show that S1PR1, a receptor for the blood-borne bioactive lipid sphingosine-1-phosphate (S1P), is critical for inhibition of angiogenesis and acquisition of vascular stability. Loss of S1PR1 leads to increased endothelial cell sprouting and the formation of ectopic vessel branches. Conversely, S1PR1 signaling inhibits angiogenic sprouting and enhances cell-to-cell adhesion. This correlates with inhibition of vascular endothelial growth factor-A (VEGF-A)-induced signaling and stabilization of vascular endothelial (VE)-cadherin localization at endothelial junctions. Our data suggest that S1PR1 signaling acts as a vascular-intrinsic stabilization mechanism, protecting developing blood vessels against aberrant angiogenic responses.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-182752 (URN)10.1016/j.devcel.2012.08.005 (DOI)000308776400015 ()
Available from: 2012-10-18 Created: 2012-10-15 Last updated: 2017-12-07Bibliographically approved
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