EphB2 and ephrin-B1 expressed in the adult kidney regulate the cytoarchitecture of medullary tubule cells through Rho family GTPases

Ogawa, Kazushige; Wada, Hiroki; Okada, Noriyoshi; Harada, Itsuki; Nakajima, Takayuki; Pasquale, Elena B.; Tsuyama, Shingo

doi:10.1242/jcs.02777

Cited by 51 publications

(53 citation statements)

References 51 publications

(60 reference statements)

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“…EphB2/ephrin B1 signaling has been implicated in regulation of the cytoarchitecture of medullary tubule cells (Ogawa et al, 2006) and reverse signaling mediated by ephrin B2 and EphB2 in the orchestration of urorectal septation (Dravis et al, 2004). Here, we provide evidence that Eph/ephrin signaling also plays a crucial role in establishing ureter-bladder connectivity.…”

Section: Introductionmentioning

confidence: 62%

Nephric duct insertion requires EphA4/EphA7 signaling from the pericloacal mesenchyme

et al. 2014

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The vesico-ureteric junction (VUJ) forms through a complex developmental program that connects the primordium of the upper urinary tract [the nephric duct (ND)] with that of the lower urinary tract (the cloaca). The signals that orchestrate the various tissue interactions in this program are poorly understood. Here, we show that two members of the EphA subfamily of receptor tyrosine kinases, EphA4 and EphA7, are specifically expressed in the mesenchyme surrounding the caudal ND and the cloaca, and that Epha4+/− and Epha4 −/− ;Epha7 −/− (DKO) mice display distal ureter malformations including ureterocele, blind and ectopically ending ureters with associated hydroureter, megaureter and hydronephrosis. We trace these defects to a late or absent fusion of the ND with the cloaca. In DKO embryos, the ND extends normally and approaches the cloaca but the tip subsequently looses its integrity. Expression of Gata3 and Lhx1 and their downstream target Ret is severely reduced in the caudal ND. Conditional deletion of ephrin B2 from the ND largely phenocopies these changes, suggesting that EphA4/EphA7 from the pericloacal mesenchyme signal via ephrin B2 to mediate ND insertion. Disturbed activity of this signaling module may entail defects of the VUJ, which are frequent in the spectrum of congenital anomalies of the kidney and the urinary tract (CAKUT) in human newborns.

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Section: Introductionmentioning

confidence: 62%

Nephric duct insertion requires EphA4/EphA7 signaling from the pericloacal mesenchyme

et al. 2014

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“…Thus, the decrease of CM width may probably indirectly relax the desmin network attached to the lateral membrane thus mimicking CM features observed in the absence of desmin. 24,25 Previous studies have already suggested a role for ephrin-B1 in the maintenance of cytomorphology of epithelial cells in the adult kidney, 12 as well as for other members from eph/ephrin family in different tissues. 13,14 However, our data provide first evidence for its importance in stabilization of cardiac tissue architecture independently of cell-cell interaction given the absence of CMs connection through the lateral membrane where it is specifically expressed.…”

Section: Discussionmentioning

confidence: 99%

“…Ephrin-B1 expression at the lateral membrane of the CM occurs only following the first postnatal days and only during the CM terminal differentiation process (postnatal days [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] when it acquires its characteristic rod-shape morphology. Because the lateral membrane of the adult CM is required for maintenance of its characteristic rod-like shape, its modification in the ephrin-B1 KO mice could alter the paving shape of the CM as readily observed.…”

Section: Discussionmentioning

confidence: 99%

“…9 So far, little is known regarding their putative roles in adult tissue but they have been reported to participate in modulation of bone remodeling 10 and insulin secretion. 11 Finally, their role in the control of cell-cell interactions has been underlined in kidney 12 and crystalline lens 13 emphasizing the importance of ephrin system in maintaining tissue architecture.…”

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confidence: 99%

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Ephrin-B1 Is a Novel Specific Component of the Lateral Membrane of the Cardiomyocyte and Is Essential for the Stability of Cardiac Tissue Architecture Cohesion

Genet

Guilbeau‐Frugier

Honton

et al. 2012

Circulation Research

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Rationale: Cardiac tissue cohesion relying on highly ordered cardiomyocytes (CM) interactions is critical because most cardiomyopathies are associated with tissue remodeling and architecture alterations.Objective: Eph/ephrin system constitutes a ubiquitous system coordinating cellular communications which recently emerged as a major regulator in adult organs. We examined if eph/ephrin could participate in cardiac tissue cyto-organization. Methods and Results:We reported the expression of cardiac ephrin-B1 in both endothelial cells and for the first time in CMs where ephrin-B1 localized specifically at the lateral membrane. Ephrin-B1 knock-out (KO) mice progressively developed cardiac tissue disorganization with loss of adult CM rod-shape and sarcomeric and intercalated disk structural disorganization confirmed in CM-specific ephrin-B1 KO mice. CMs lateral membrane exhibited abnormal structure by electron microscopy and notably increased stiffness by atomic force microscopy. In wild-type CMs, ephrin-B1 interacted with claudin-5/ZO-1 complex at the lateral membrane, whereas the complex disappeared in KO/CM-specific ephrin-B1 KO mice. Ephrin-B1 deficiency resulted in decreased mRNA expression of CM basement membrane components and disorganized fibrillar collagen matrix, independently of classical integrin/dystroglycan system. KO/CM-specific ephrin-B1 KO mice exhibited increased left ventricle diameter and delayed atrioventricular conduction. Under pressure overload stress, KO mice were prone to death and exhibited striking tissue disorganization. Finally, failing CMs displayed downregulated ephrin-B1/claudin-5 gene expression linearly related to the ejection fraction. Conclusions:Ephrin-B1 is necessary for cardiac tissue architecture cohesion by stabilizing the adult CM morphology through regulation of its lateral membrane. Because decreased ephrin-B1 is associated with molecular/functional cardiac defects, it could represent a new actor in the transition toward heart failure. (Circ Res. 2012;110:688-700.) Key Words: cardiomyocyte Ⅲ extracellular matrix Ⅲ lateral membrane Ⅲ cardiac tissue Ⅲ architecture Ⅲ heart failure T he heart constitutes a particular compact organ relying on strong tissue architecture cohesion and tight cellular interactions that ensure both mechanical and electrochemical coupling. Thus, most cardiopathies are associated with cardiac tissue remodeling and with alterations in architecture involved in disease progression toward heart failure (HF).Despite considerable advances in the field and development of effective drugs, HF still remains a prevalent condition associated with high morbidity and mortality rates. This could be in part explained by still imperfect knowledge of molecular basis at the origin of HF. In fact, to date, most research has focused on cardiomyocyte (CM) contractile dysfunction Original received December 15, 2011; revision received January 16, 2012; accepted January 25, 2012. In December 2011, the average time from submission to first decision for all original research pape...

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“…These consist of cytoskeleton-dependent events where the ephrins and their receptors shape organs such as the colon (Batlle et al, 2002) and kidney (Ogawa et al, 2006). They were first discovered as the major modulators of axonal guidance, neurite outgrowth, dendritic spine morphogenesis, vasculogenesis, and cellular repulsion (Pasquale, 2005).…”

Section: Introductionmentioning

confidence: 99%

The Synovial Sarcoma SYT-SSX2 Oncogene Remodels the Cytoskeleton through Activation of the Ephrin Pathway

Barco

Hunt²,

Frump³

et al. 2007

MBoC

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Synovial sarcoma is a soft tissue cancer associated with a recurrent t(X:18) translocation that generates one of two fusion proteins, SYT-SSX1 or SYT-SSX2. In this study, we demonstrate that SYT-SSX2 is a unique oncogene. Rather than confer enhanced proliferation on its target cells, SYT-SSX2 instead causes a profound alteration of their architecture. This aberrant morphology included elongation of the cell body and formation of neurite-like extensions. We also observed that cells transduced with SYT-SSX2 often repulsed one another. Notably, cell repulsion is a known component of ephrin signaling. Further analysis of SYT-SSX2-infected cells revealed significant increases in the expression and activation of Eph/ephrin pathway components. On blockade of EphB2 signaling SYT-SSX2 infectants demonstrated significant reversion of the aberrant cytoskeletal phenotype. In addition, we discovered, in parallel, that SYT-SSX2 induced stabilization of the microtubule network accompanied by accumulation of detyrosinated Glu tubulin and nocodazole resistance. Glu tubulin regulation was independent of ephrin signaling. The clinical relevance of these studies was confirmed by abundant expression of both EphB2 and Glu tubulin in SYT-SSX2-positive synovial sarcoma tissues. These results indicate that SYT-SSX2 exerts part of its oncogenic effect by altering cytoskeletal architecture in an Eph-dependent manner and cytoskeletal stability through a concurrent and distinct pathway.

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EphB2 and ephrin-B1 expressed in the adult kidney regulate the cytoarchitecture of medullary tubule cells through Rho family GTPases

Cited by 51 publications

References 51 publications

Nephric duct insertion requires EphA4/EphA7 signaling from the pericloacal mesenchyme

Nephric duct insertion requires EphA4/EphA7 signaling from the pericloacal mesenchyme

Ephrin-B1 Is a Novel Specific Component of the Lateral Membrane of the Cardiomyocyte and Is Essential for the Stability of Cardiac Tissue Architecture Cohesion

The Synovial Sarcoma SYT-SSX2 Oncogene Remodels the Cytoskeleton through Activation of the Ephrin Pathway

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