Biology subjects

Rinker, K. D.

Publications and source records attributed to Rinker, K. D..

2 recordsLinked to original sources

bioRxiv2021

Venous activation of MEK/ERK drives development of arteriovenous malformation and blood 2 flow anomalies with loss of Rasa1

Vascular malformations develop when growth pathway signaling goes awry in the endothelial cells lining blood vessels. Arteriovenous malformations (AVMs) arise where arteries and veins abnormally connect in patients with loss of RASA1, a Ras GTPase activating protein, and, as we show here, in zebrafish rasa1 mutants. Mutant fish develop massively enlarged vessels at the connection between artery and vein in the tail vascular plexus. These AVMs progressively enlarge and become filled with slow-flowing blood and have a greater drop in pulsatility from the artery to the vein. Expression of the flow responsive transcription factor klf2a is diminished in rasa1 mutants, suggesting changes in flow velocity and pattern contribute to the progression of vessel malformations. Migration of endothelial cells is not affected in rasa1 mutants, nor is cell death or proliferation. Early developmental artery-vein patterning is also normal in rasa1 mutants, but we find that MEK/ERK signaling is ectopically activated in the vein as compared to high arterial activation seen in wildtype animals. MEK/ERK signaling inhibition prevents AVM development of rasa1 mutants, demonstrating venous MEK/ERK drives the initiation of rasa1 AVMs. Thus, rasa1 mutants show overactivation of MEK/ERK signaling causes AVM formation, altered blood flow and downstream flow responsive signaling. SummaryThe zebrafish model of RASA1 capillary malformation and arteriovenous malformation (CM-AVM1) develops cavernous vascular malformations driven by ectopic MEK/ERK signaling in the vein, disrupting flow and downstream mechanosensitive signaling.

developmental biology↗

bioRxiv2020

Viral manipulation of a novel mechanoresponsive signalling axis disassembles processing bodies

Processing bodies (PBs) are ribonucleoprotein granules that suppress cytokine mRNA translation that are targeted for disassembly by many viruses. Kaposis sarcoma-associated herpesvirus is the etiological agent of the inflammatory endothelial cancer, Kaposis sarcoma, and a PB-regulating virus. The virus encodes Kaposin B (KapB), which induces actin stress fibres (SFs) and cell spindling as well as PB disassembly. We now show that KapB-mediated PB disassembly requires actin rearrangements, RhoA effectors and the mechanoresponsive transcription activator, YAP. Moreover, ectopic expression of active YAP or exposure of ECs to mechanical forces caused PB disassembly in the absence of KapB and mechanoresponsive PB disassembly also required YAP. Using the viral protein KapB, we identified a new consequence of the exposure of cells to mechanical forces that alter actin dynamics and activate YAP, namely the disassembly of PBs. ImportanceFor the first time, we demonstrate that processing bodies (PBs), cytoplasmic sites of RNA decay, are regulated by mechanical signaling events that alter actin dynamics and that this requires the mechanoresponsive transcription factor, YAP. Using the overexpression of a viral protein called KapB, known previously to mediate PB disassembly, we show that actin stress fibers (SFs) and the mechanoresponsive transcription factor, YAP, are required for PB loss. We also show that other established mechanical signals (shear stress or stiff extracellular matrix) that lead to the formation of SFs and activate YAP also cause PB disassembly. This is important because it means that KapB activates, from the inside out, a pathway that links cell shape to post-transcriptional gene regulation via cytoplasmic PBs.

cell biology↗