title: Missense Mutation of POU Domain Class 3 Transcription Factor 3 in Pou3f3L423P Mice Causes Reduced Nephron Number and Impaired Development of the Thick Ascending Limb of the Loop of Henle.
abstract: During nephrogenesis, POU domain class 3 transcription factor 3 (POU3F3 aka BRN1) is critically involved in development of distinct nephron segments, including the thick ascending limb of the loop of Henle (TAL). Deficiency of POU3F3 in knock-out mice leads to underdevelopment of the TAL, lack of differentiation of TAL cells, and perinatal death due to renal failure. Pou3f3L423P mutant mice, which were established in the Munich ENU Mouse Mutagenesis Project, carry a recessive point mutation in the homeobox domain of POU3F3. Homozygous Pou3f3L423P mutants are viable and fertile. The present study used functional, as well as qualitative and quantitative morphological analyses to characterize the renal phenotype of juvenile (12 days) and aged (60 weeks) homo- and heterozygous Pou3f3L423P mutant mice and age-matched wild-type controls. In both age groups, homozygous mutants vs. control mice displayed significantly smaller kidney volumes, decreased nephron numbers and mean glomerular volumes, smaller TAL volumes, as well as lower volume densities of the TAL in the kidney. No histological or ultrastructural lesions of TAL cells or glomerular cells were observed in homozygous mutant mice. Aged homozygous mutants displayed increased serum urea concentrations and reduced specific urine gravity, but no evidence of glomerular dysfunction. These results confirm the role of POU3F3 in development and function of the TAL and provide new evidence for its involvement in regulation of the nephron number in the kidney. Therefore, Pou3f3L423P mutant mice represent a valuable research model for further analyses of POU3F3 functions, or for nephrological studies examining the role of congenital low nephron numbers.
authors.affiliation: Institute of Veterinary Pathology at the Centre for Clinical Veterinary Medicine, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Rieger
authors.affiliation: Chair for Molecular Animal Breeding and Biotechnology and Laboratory for Functional Genome Analysis, Gene Center, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kemter
authors.affiliation: Chair for Molecular Animal Breeding and Biotechnology and Laboratory for Functional Genome Analysis, Gene Center, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Sudhir
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Department of Anatomy and Cell Biology, Biomedical Center, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Bastian
authors.initials: B
authors.lastname: Popper
authors.affiliation: Chair for Molecular Animal Breeding and Biotechnology and Laboratory for Functional Genome Analysis, Gene Center, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Aigner
authors.affiliation: Chair for Molecular Animal Breeding and Biotechnology and Laboratory for Functional Genome Analysis, Gene Center, Ludwig-Maximilians-Universität München, Munich, Germany.|German Center for Diabetes Research (DZD), Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Eckhard
authors.initials: E
authors.lastname: Wolf
authors.affiliation: Institute of Veterinary Pathology at the Centre for Clinical Veterinary Medicine, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Wanke
authors.affiliation: Institute of Veterinary Pathology at the Centre for Clinical Veterinary Medicine, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Blutke
mesh_terms: D000818:Animals; D001794:Blood Pressure; D001835:Body Weight; D005260:Female; D007668:Kidney / Q000002:abnormalities* / Q000254:growth & development* / Q000378:metabolism; D008138:Loop of Henle / Q000002:abnormalities / Q000254:growth & development / Q000378:metabolism; D008297:Male; D051379:Mice; D020125:Mutation, Missense; D009399:Nephrons / Q000002:abnormalities / Q000254:growth & development / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009929:Organ Size; D050809:POU Domain Factors / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D009419:Nerve Tissue Proteins; D050809:POU Domain Factors; D012333:RNA, Messenger; C074065:Pou3f3 protein, mouse