title: The podocyte-specific inactivation of Lmx1b, Ldb1 and E2a yields new insight into a transcriptional network in podocytes.
abstract: Patients with nail-patella syndrome, which among other symptoms also includes podocyte-associated renal failure, suffer from mutations in the LMX1B gene. The disease severity among patients is quite variable and has given rise to speculations on the presence of modifier genes. Promising candidates for modifier proteins are the proteins interacting with LMX1B, such as LDB1 and E47. Since human kidney samples from patients are difficult to obtain, conventional Lmx1b knock-out mice have been extremely valuable to study the role of Lmx1b in podocyte differentiation. In contrast to findings in these mice, however, in which a downregulation of the Col4a3, Col4a4 and Nphs2 genes has been described, no such changes have been detected in kidney biopsies from patients. We now report on our results on the characterization of constitutive podocyte-specific Lmx1b, Ldb1 and E2a knock-out mice. Constitutive podocyte-specific Lmx1b knock-out mice survive for approximately 2 weeks after birth and do not present with a downregulation of the Col4a3, Col4a4 and Nphs2 genes, therefore they mimic the human disease more closely. The podocyte-specific Ldb1 knock-out mice survive longer, but then also succumb to renal failure, whereas the E2a knock-out mice show no renal symptoms for at least 6 months after birth. We conclude that LDB1, but not E2A is a promising candidate as a modifier gene in patients with nail-patella syndrome.
authors.affiliation: University of Regensburg, Institute for Molecular and Cellular Anatomy, Universitätsstr. 31, 93053 Regensburg, and Division of Nephrology and Immunology, University Hospital, RWTH, Aachen, Germany.
authors.forename: Hani
authors.initials: H
authors.lastname: Suleiman
authors.forename: Daniel
authors.initials: D
authors.lastname: Heudobler
authors.forename: Anne-Sarah
authors.initials: AS
authors.lastname: Raschta
authors.forename: Yangu
authors.initials: Y
authors.lastname: Zhao
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhao
authors.forename: Irmgard
authors.initials: I
authors.lastname: Hertting
authors.forename: Helga
authors.initials: H
authors.lastname: Vitzthum
authors.forename: Marcus J
authors.initials: MJ
authors.lastname: Moeller
authors.forename: Lawrence B
authors.initials: LB
authors.lastname: Holzman
authors.forename: Reinhard
authors.initials: R
authors.lastname: Rachel
authors.forename: Randy
authors.initials: R
authors.lastname: Johnson
authors.forename: Heiner
authors.initials: H
authors.lastname: Westphal
authors.forename: Anne
authors.initials: A
authors.lastname: Rascle
authors.forename: Ralph
authors.initials: R
authors.lastname: Witzgall
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D060588:LIM Domain Proteins; D060850:LIM-Homeodomain Proteins; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009261:Nail-Patella Syndrome / Q000378:metabolism / Q000473:pathology; D009399:Nephrons / Q000378:metabolism / Q000473:pathology; D050199:Podocytes / Q000502:physiology*; D051381:Rats; D051437:Renal Insufficiency / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D060588:LIM Domain Proteins; D060850:LIM-Homeodomain Proteins; D014157:Transcription Factors; C112149:LIM homeobox transcription factor 1 beta; C102084:Ldb1 protein, mouse; C075668:Tcf3 protein, mouse