The LIM-homeodomain transcription factor Lmx1b plays a crucial role in podocytes.
Patients with nail-patella syndrome often suffer from a nephropathy, which ultimately results in chronic renal failure. The finding that this disease is caused by mutations in the transcription factor LMX1B, which in the kidney is expressed exclusively in podocytes, offers the opportunity for a better understanding of the renal pathogenesis. In our analysis of the nephropathy in nail-patella syndrome, we have made use of the Lmx1b knockout mouse. Transmission electron micrographs showed that glomerular development in general and the differentiation of podocytes in particular were severely impaired. The glomerular capillary network was poorly elaborated, fenestrae in the endothelial cells were largely missing, and the glomerular basement membrane was split. In addition podocytes retained a cuboidal shape and did not form foot processes and slit diaphragms. Expression of the alpha4 chain of collagen IV and of podocin was also severely reduced. Using gel shift assays, we demonstrated that LMX1B bound to two AT-rich sequences in the promoter region of NPHS2, the gene encoding podocin. Our results demonstrate that Lmx1b regulates important steps in glomerular development and establish a link between three hereditary kidney diseases: nail-patella syndrome (Lmx1b), steroid-resistant nephrotic syndrome (podocin), and Alport syndrome (collagen IV alpha4).
Rohr
Claudia
C
Institute for Anatomy and Cell Biology I, University of Heidelberg, Im Neuenheimer Feld 307, 69120 Heidelberg, Germany.
Prestel
Jürgen
J
Heidet
Laurence
L
Hosser
Hiltraud
H
Kriz
Wilhelm
W
Johnson
Randy L
RL
Antignac
Corinne
C
Witzgall
Ralph
R
D000818:Animals; D000831:Animals, Newborn; D001483:Base Sequence; D002454:Cell Differentiation / Q000502:physiology; D024141:Collagen Type IV / Q000235:genetics; D015870:Gene Expression; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007678:Kidney Glomerulus / Q000166:cytology*; D060850:LIM-Homeodomain Proteins; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D009154:Mutation; D009261:Nail-Patella Syndrome / Q000235:genetics / Q000473:pathology; D009394:Nephritis, Hereditary / Q000235:genetics; D009404:Nephrotic Syndrome / Q000235:genetics; D010641:Phenotype; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D024141:Collagen Type IV; D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; C112149:LIM homeobox transcription factor 1 beta; D060850:LIM-Homeodomain Proteins; D008565:Membrane Proteins; C407223:NPHS2 protein; D012333:RNA, Messenger; D014157:Transcription Factors