Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0403608 (ureter)
 9,655 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Discs-large homolog 1 (DLGH1) is a mouse ortholog of the Drosophila discs-large (DLG) tumor suppressor protein, a founding member of the PDZ and MAGUK protein families. DLG proteins play important roles in regulating cell proliferation, epithelial cell polarity, and synapse formation and function. Here, we generated a null allele of Dlgh1 and studied its role in urogenital development. Dlgh1(-/-) mice developed severe urinary tract abnormalities, including congenital hydronephrosis, which is the leading cause of renal failure in infants and children. DLGH1 is expressed in the developing ureter; in its absence, the stromal cells that normally lie between the urothelial and smooth muscle layers were missing. Moreover, in ureteric smooth muscle, the circular smooth muscle cells were misaligned in a longitudinal orientation. These abnormalities in the ureter led to severely impaired ureteric peristalsis. Similar smooth muscle defects are observed frequently in patients with ureteropelvic junction obstruction, a common form of hydronephrosis. Our results suggest that (i) besides its well documented role in regulating epithelial polarity, Dlgh1 also regulates smooth muscle orientation, and (ii) human DLG1 mutations may contribute to hereditary forms of hydronephrosis.
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PMID:Discs-large homolog 1 regulates smooth muscle orientation in the mouse ureter. 1717 48

Congenital anomalies of the kidney and urinary tract occur at a frequency of 1 in 500 live births in humans. Mutant mice null for Dlg1 (Dlg1(-/-) mice), a membrane-associated guanylate kinase containing PDZ domains, exhibit various urogenital malformations, including hypoplasia of the kidney and ureter, megaureter, hydronephrosis, and aplasia of the seminal vesicle and the vagina. The common nephric duct (CND) is a distal part of the Wolffian duct between the ureteric branch and the opening to the urogenital sinus, and normally disappears by embryonic day (E) 12.5 by a downward shift of the ureteric branch. Although retardation of the disappearance of the CND is apparent during urogenital development in Dlg1(-/-) mice, its pathogenesis and prognosis are unclear. In the present study, we found a decrease in apoptotic cells in the CND epithelium in Dlg1(-/-) mice at E11.5. Cell proliferation did not change. Additionally, histological observation of the development of the ureteral orifice indicated that the CND remained at E15.5 and was widely open to the vesical lumen in Dlg1(-/-) mice, in contrast to the complete disappearance of the CND and a narrow ureteric orifice in control mice. The dilatation of the vesicoureteral junction remained at E18.5. Opening of the vesicoureteral junction is known to cause vesicoureteral reflux and subsequent megaureter and hydronephrosis. Therefore, our present observation demonstrates that lack of the Dlg1 gene induces a decrease in apoptotic epithelial cell death and the persistence of the CND, which result in a dysfunctional vesicoureteral junction and cause megaureter or hydronephrosis through vesicoureteral reflux.
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PMID:Decreased apoptosis and persistence of the common nephric duct during the development of an aberrant vesicoureteral junction in Dlg1 gene-targeted mice. 2414 60