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Abnormal renal phenotype in L1 knockout mice: a novel cause of CAKUT
Hanna Debiec1, Michael Kutsche, Melitta Schachner
1INSERM U489, Hôpital Tenon and Université Paris 6, Paris, France.
Abstract:
L1, a member of the immunoglobulin superfamily, is a cell adhesion and signal transducing molecule. In the kidney, L1 is expressed in the mesonephric duct and the metanephros throughout collecting duct development. We show that mice with a targeted deletion of the L1 gene display diverse renal malformations including (i) a duplex kidney with two ureters partially or totally separated, accompanied by hydronephrosis; and (ii) an enlarged elongated kidney with a malformed or incorrectly positioned inner medulla. The type, penetrance and severity of these phenotypes are influenced by the genetic background. The development of a duplex kidney is initiated by double ureteral budding from the Wolffian duct or by an accessory budding from the main ureter, whereas medullary malformation is due to an improper growth and branching pattern of ureteral branches. Multiple developmental defects in formation of the collecting system promote subsequent renal damage and progression to renal insufficiency. Various features of mouse ureteral duplication resemble the human congenital anomalies of the kidney and urinary tract (CAKUT) although disturbances of medulla development have not yet been reported in men.
Insights
Targeted deletion of the L1 gene in mice causes diverse kidney malformations, including duplex kidneys and medullary defects. These findings offer insights into congenital anomalies of the kidney and urinary tract (CAKUT).
Area of Science:
- Developmental biology
- Genetics
- Nephrology
Background:
- L1, an immunoglobulin superfamily member, functions as a cell adhesion and signal transducing molecule.
- L1 is expressed in the developing kidney, specifically in the mesonephric duct and metanephros during collecting duct formation.
Purpose of the Study:
- To investigate the role of L1 in kidney development.
- To characterize renal malformations resulting from L1 gene deletion.
Main Methods:
- Targeted deletion of the L1 gene in mice.
- Phenotypic analysis of renal malformations in L1-deficient mice.
- Examination of ureteral budding and branching patterns.
Main Results:
- L1 gene deletion led to diverse renal malformations, including duplex kidneys with hydronephrosis and enlarged kidneys with medullary defects.
- The severity and type of malformations were influenced by the genetic background.
- Duplex kidney development was linked to abnormal ureteral budding, while medullary malformations resulted from improper ureteral branching.
Conclusions:
- L1 plays a critical role in normal kidney development, particularly in collecting system formation.
- L1 deficiency causes complex renal anomalies, some resembling human congenital anomalies of the kidney and urinary tract (CAKUT).
- Further research is needed to explore the potential role of L1 in human CAKUT, especially medullary development disturbances.