Networks that link cytoskeletal regulators and diaphragm proteins underpin filtration function in Drosophila nephrocytes

Muraleedharan, Simi; Sam, Aksah; Skaer, Helen; Inamdar, Maneesha S.

doi:10.1016/j.yexcr.2018.02.015

Cited by 11 publications

(8 citation statements)

References 51 publications

(68 reference statements)

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“…In our case, TEM images did not show any effect in ND number, probably because the reduction in s ns expression of IR-Rph nephrocytes was only 20%. Accordingly, recent studies have documented the significance of cytoplasmic Sns in regulating actin organization ( Muraleedharan et al, 2016 ), which could be direct or a result of altered cortical actin when ND proteins are lost or reduced. The same study highlights the role of the reciprocal regulation between cytoskeletal components and ND proteins as essential for size and charge-dependent filtration.…”

Section: Discussionmentioning

confidence: 99%

Rabphilin involvement in filtration and molecular uptake in Drosophila nephrocytes suggests a similar role in human podocytes

Selma-Soriano

Llamusí

Fernández‐Costa

et al. 2020

Disease Models &Amp; Mechanisms

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Drosophila nephrocytes share functional, structural and molecular similarities with human podocytes. It is known that podocytes express the rabphilin 3A (RPH3A)-RAB3A complex, and its expression is altered in mouse and human proteinuric disease. Furthermore, we previously identified a polymorphism that suggested a role for RPH3A protein in the development of urinary albumin excretion. As endocytosis and vesicle trafficking are fundamental pathways for nephrocytes, the objective of this study was to assess the role of the RPH3A orthologue in Drosophila, Rabphilin (Rph), in the structure and function of nephrocytes. We confirmed that Rph is required for the correct function of the endocytic pathway in pericardial Drosophila nephrocytes. Knockdown of Rph reduced the expression of the cubilin and stick and stones genes, which encode proteins that are involved in protein uptake and filtration. We also found that reduced Rph expression resulted in a disappearance of the labyrinthine channel structure and a reduction in the number of endosomes, which ultimately leads to changes in the number and volume of nephrocytes. Finally, we demonstrated that the administration of retinoic acid to IR-Rph nephrocytes rescued some altered aspects, such as filtration and molecular uptake, as well as the maintenance of cell fate. According to our data, Rph is crucial for nephrocyte filtration and reabsorption, and it is required for the maintenance of the ultrastructure, integrity and differentiation of the nephrocyte.

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Section: Discussionmentioning

confidence: 99%

Rabphilin involvement in filtration and molecular uptake in Drosophila nephrocytes suggests a similar role in human podocytes

Selma-Soriano

Llamusí

Fernández‐Costa

et al. 2020

Disease Models &Amp; Mechanisms

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“…PI(4,5)P2 as well as PI(3,4,5)P3 are capable of regulating the actin cytoskeleton by recruiting and activating the small GTPases Rac1 and Cdc42 as well as proteins of the WASP family [ 21 – 23 ]. Notably, a coordinated actin cytoskeleton remodeling is essential for cortical Nephrin localization and slit diaphragm assembly in Drosophila nephrocytes [ 61 , 62 ] as well as in mammalian podocytes [ 63 ]. Vice versa, activated Nephrin recruits PI3K resulting in Rac1 activation, actin branching and lamellipodia formation in cultured rat podocytes [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

PI(4,5)P2 controls slit diaphragm formation and endocytosis in Drosophila nephrocytes

Gass

Borkowsky

Lotz

et al. 2022

Cell. Mol. Life Sci.

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Drosophila nephrocytes are an emerging model system for mammalian podocytes and proximal tubules as well as for the investigation of kidney diseases. Like podocytes, nephrocytes exhibit characteristics of epithelial cells, but the role of phospholipids in polarization of these cells is yet unclear. In epithelia, phosphatidylinositol(4,5)bisphosphate (PI(4,5)P2) and phosphatidylinositol(3,4,5)-trisphosphate (PI(3,4,5)P3) are asymmetrically distributed in the plasma membrane and determine apical–basal polarity. Here, we demonstrate that both phospholipids are present in the plasma membrane of nephrocytes, but only PI(4,5)P2 accumulates at slit diaphragms. Knockdown of Skittles, a phosphatidylinositol(4)phosphate 5-kinase, which produces PI(4,5)P2, abolished slit diaphragm formation and led to strongly reduced endocytosis. Notably, reduction in PI(3,4,5)P3 by overexpression of PTEN or expression of a dominant-negative phosphatidylinositol-3-kinase did not affect nephrocyte function, whereas enhanced formation of PI(3,4,5)P3 by constitutively active phosphatidylinositol-3-kinase resulted in strong slit diaphragm and endocytosis defects by ectopic activation of the Akt/mTOR pathway. Thus, PI(4,5)P2 but not PI(3,4,5)P3 is essential for slit diaphragm formation and nephrocyte function. However, PI(3,4,5)P3 has to be tightly controlled to ensure nephrocyte development.

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“…PI(4,5)P2 as well as PI(3,4,5)P3 are capable of regulating the actin cytoskeleton by recruiting and activating the small GTPases Rac1 and Cdc42 as well as proteins of the WASP family (Prehoda et al, 2000;Rohatgi et al, 2000;Padrick and Rosen, 2010). Notably, a coordinated actin cytoskeleton remodeling is essential for cortical Nephrin localization and slit diaphragm assembly in Drosophila nephrocytes (Muraleedharan et al, 2018;Bayraktar et al, 2020) as well as in mammalian podocytes (Perico et al, 2016). Vice versa, activated Nephrin recruits PI3K resulting in Rac1 activation, actin branching and lamellipodia formation in cultured rat podocytes (Zhu et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

PI(4,5)P2 controls slit diaphragm formation and endocytosis in Drosophila nephrocytes

Gass

Borkowsky

Lotz

et al. 2021

Preprint

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Drosophila nephrocytes are an emerging model system for mammalian podocytes and podocyte-associated diseases. Like podocytes, nephrocytes exhibit characteristics of epithelial cells, but the role of phospholipids in polarization of these cells is yet unclear. In epithelia phosphatidylinositol(4,5)bisphosphate (PI(4,5)P2) and phosphatidylinositol(3,4,5)-trisphosphate (PI(3,4,5)P3) are asymmetrically distributed in the plasma membrane and determine apical-basal polarity. Here we demonstrate that both phospholipids are present in the plasma membrane of nephrocytes, but only PI(4,5)P2 accumulates at slit diaphragms. Knockdown of Skittles, a phosphatidylinositol(4)phosphate 5-kinase, which produces PI(4,5)P2, abolished slit diaphragm formation and led to strongly reduced endocytosis. Notably, reduction in PI(3,4,5)P3 by overexpression of PTEN or expression of a dominant-negative phosphatidylinositol-3-Kinase did not affect nephrocyte function, whereas enhanced formation of PI(3,4,5)P3 by constitutively active phosphatidylinositol-3-Kinase resulted in strong slit diaphragm and endocytosis defects by ectopic activation of the Akt/mTOR pathway. Thus, PI(4,5)P2 but not PI(3,4,5)P3 is essential for slit diaphragm formation and nephrocyte function. However, PI(3,4,5)P3 has to be tightly controlled to ensure nephrocyte development.

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Networks that link cytoskeletal regulators and diaphragm proteins underpin filtration function in Drosophila nephrocytes

Cited by 11 publications

References 51 publications

Rabphilin involvement in filtration and molecular uptake in Drosophila nephrocytes suggests a similar role in human podocytes

Rabphilin involvement in filtration and molecular uptake in Drosophila nephrocytes suggests a similar role in human podocytes

PI(4,5)P2 controls slit diaphragm formation and endocytosis in Drosophila nephrocytes

PI(4,5)P2 controls slit diaphragm formation and endocytosis in Drosophila nephrocytes

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