WT1 activates a glomerular-specific enhancer identified from the human nephrin gene.
The glomerular filtration barrier separates the blood from the urinary space. Nephrin is a transmembrane protein that belongs to the immunoglobulin superfamily and is localized to the slit diaphragms that are a critical component of this filtration barrier. Mutations in the nephrin gene (NPHS1) lead to congenital Finnish nephropathy, whereas alterations in the level of nephrin expression have been identified in a wide range of acquired glomerular diseases. A 186-bp fragment from the human NPHS1 promoter is capable of directing podocyte-specific expression of a beta-galactosidase transgene when placed in front of a heterologous minimal promoter in transgenic mice. The Wilms tumor suppressor gene (WT1) is a zinc-finger-containing transcription factor that is coexpressed with NPHS1 in differentiated podocytes; gel shift binding assays demonstrate that a recombinant WT1 protein can bind and activate the 186-bp NPHS1 fragment in a sequence-specific manner. Taken together, these results suggest that WT1 may be required for regulation of the NPHS1 gene in vivo.
Guo
Gordon
G
Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
Morrison
Debra J
DJ
Licht
Jonathan D
JD
Quaggin
Susan E
SE
D000818:Animals; D004742:Enhancer Elements, Genetic / Q000187:drug effects* / Q000502:physiology; D015870:Gene Expression; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D007678:Kidney Glomerulus / Q000378:metabolism*; D007763:Lac Operon / Q000235:genetics; D008156:Luciferases / Q000235:genetics; D008565:Membrane Proteins; D051379:Mice; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D011506:Proteins / Q000235:genetics*; D019076:Transgenes / Q000187:drug effects; D025721:WT1 Proteins / Q000494:pharmacology* / Q000502:physiology; D001616:beta-Galactosidase / Q000378:metabolism
D008565:Membrane Proteins; D011506:Proteins; D025721:WT1 Proteins; C113267:nephrin; D008156:Luciferases; D001616:beta-Galactosidase