Willin, an upstream component of the Hippo signaling pathway, orchestrates mammalian peripheral nerve fibroblasts

Willin/FRMD6 was first identified in the rat sciatic nerve, which is composed of neurons, Schwann cells, and fibroblasts. Willin is an upstream component of the Hippo signaling pathway, which results in the inactivation of the transcriptional coactivator YAP through Ser127 phosphorylation. This in turn suppresses the expression of genes involved in cell growth, proliferation and cancer development ensuring the control of organ size, cell contact inhibition and apoptosis. Here we show that in the mammalian sciatic nerve, Willin is predominantly expressed in fibroblasts and that Willin expression activates the Hippo signaling cascade and induces YAP translocation from the nucleus to the cytoplasm. In addition within these cells, although it inhibits cellular proliferation, Willin expression induces a quicker directional migration towards scratch closure and an increased expression of factors linked to nerve regeneration. These results show that Willin modulates sciatic nerve fibroblast activity indicating that Willin may have a potential role in the regeneration of the peripheral nervous system.Publisher PDFPeer reviewe

Abstract 2831: Endomyocardial-to-Epimyocardial Blood Flow Ratio Distinguishes Severity of Coronary Artery Disease: A Perfusion CMR Study

Background: Ischemia propagates as a wave front from the endocardial (ENDO) to the epicardial (EPI) surface. Normally, myocardial blood flow (MBF) is higher in the ENDO than EPI. We hypothesized that the ENDO/EPI ratio could differentiate the severity of coronary stenoses in a clinical patient population. Methods: Perfusion CMR was performed in 29 patients within 30 days of x-ray angiography and quantitative coronary analysis. During adenosine infusion and at rest, dual boluses of Gd-DTPA were infused (4ml/s) to quantify arterial input function (0.0075mM/kg) and tissue perfusion (0.075mM/kg) in 3 short axis slices using hybrid gradient echo/echo planar imaging. ENDO and EPI MBF for rest and stress were estimated by determining the peak amplitude of the impulse response derived from Fermi function deconvolution. Stress and rest ENDO/EPI ratios were calculated and then corrected (corr) for rate-pressure product (RPP) using the formula ENDO/EPI * (SBP*HR*10 −4 ). Results: Coronary stenosis (CS) &gt;50% was present in 23 of 29 patients. Hypertension, diabetes, and dyslipidemia were present in 23, 9, and 26 patients, respectively. Stress corrENDO/EPI (mean±SE) was inversely related to CS (CS&lt;50% = 1.356 ± 0.030, CS 50–70% = 1.266 ± 0.029, and CS&gt;70% = 1.149 ± 0.039; p&lt;0.05) (Figure ). The relationship persisted after exclusion of the 56 segments with a myocardial scar (p&lt;0.05). No relationship existed between CS and rest ENDO/EPI, rest corrENDO/EPI, or uncorrected stress ENDO/EPI. Conclusions: Stress corrENDO/EPI is inversely related to the severity of CS. Quantitative stress endo/epi ratios can distinguish intermediate from severe stenoses in patients with known or suspected CS. </jats:p