DLG1 influences distal ureter maturation via a non-epithelial cell autonomous mechanism involving reduced retinoic acid signaling, Ret expression, and apoptosis
DEVELOPMENTAL BIOLOGY
Authors: Kim, Sung Tae; Ahn, Sun-Young; Swat, Wojciech; Miner, Jeffrey H.
Abstract
The absence of Discs-large 1 (DLG1), the mouse ortholog of the Drosophila discs-large tumor suppressor, results in congenital hydronephrosis characterized by urinary tract abnormalities, reduced ureteric bud branching, and delayed disconnection of the ureter from the common nephric duct (CND). To define the specific cellular requirements for Dlg1 expression during urogenital development, we used a foxed Dlg1 allele and Pax2-Cre, Pax3-Cre, Six2-Cre, and HoxB7-Cre transgenes to generate cell type-restricted Dlg1 mutants. In addition, we used Ret(GFP) knockin and retinoic acid response element-lacZ transgenic mice to determine the effects of Dlg1 mutation on the respective morphogenetic signaling pathways. Mutation of Dlg1 in urothelium and collecting ducts (via HoxB7-Cre or Pax2-Cre) and in nephron precursors (via Pax2-Cre and Six2-Cre) resulted in no apparent abnormalities in ureteric bud branching or in distal ureter maturation, and no hydronephrosis. Mutation in nephrons, ureteric smooth muscle, and mesenchyme surrounding the lower urinary tract (via the Pax3-Cre transgene) resulted in congenital hydronephrosis accompanied by reduced branching, abnormal distal ureter maturation and insertion, and smooth muscle orientation defects, phenotypes very similar to those in Dlg1 null mice. Dlg1 null mice showed reduced Ret expression and apoptosis during ureter maturation and evidence of reduced retinoic acid signaling in the kidney. Taken together, these results suggest that Dlg1 expression in ureter and CND-associated mesenchymal cells is essential for ensuring distal ureter maturation by facilitating retinoic acid signaling, Ret expression, and apoptosis of the urothelium. (C) 2014 Elsevier Inc. All rights reserved.
The diagnostic role of BAP1 in serous effusions
HUMAN PATHOLOGY
Authors: Davidson, Ben; Totsch, Martin; Wohlschlaeger, Jeremias; Hager, Thomas; Pinamonti, Maurizio
Abstract
The aim of this study was to analyze the diagnostic role of BAP1 in effusion cytology. Effusions (n = 258), consisting of 53 malignant mesotheliomas and 205 other cancers, the majority carcinomas (62 breast, 60 ovarian, 31 lung, 51 carcinomas of other origin, 1 melanoma), were analyzed for BAP1 expression using immunohistochemistry. BAP1 was lost in 46 (87%) mesotheliomas compared with 4 (2%) of 205 other cancers (P < .001), resulting in sensitivity and specificity of 87% and 98%, respectively. There was no significant difference between peritoneal (n = 14) and pleural (n = 39) mesotheliomas. The 4 carcinomas with loss of BAP1 included 1 ovarian, 1 breast, 1 uterine cervical, and 1 gastric carcinoma. The present study supports the role of BAP1 as a highly sensitive and specific marker for malignant mesothelioma in serous effusions and argues for inclusion of this test in all specimens in which this diagnosis is considered. (C) 2018 Elsevier Inc. All rights reserved.