title: Elf5 is a principal cell lineage specific transcription factor in the kidney that contributes to Aqp2 and Avpr2 gene expression.
abstract: The mammalian kidney collecting ducts are critical for water, electrolyte and acid-base homeostasis and develop as a branched network of tubular structures composed of principal cells intermingled with intercalated cells. The intermingled nature of the different collecting duct cell types has made it challenging to identify unique and critical factors that mark and/or regulate the development of the different collecting duct cell lineages. Here we report that the canonical Notch signaling pathway components, RBPJ and Presinilin1 and 2, are involved in patterning the mouse collecting duct cell fates by maintaining a balance between principal cell and intercalated cell fates. The relatively reduced number of principal cells in Notch-signaling-deficient kidneys offered a unique genetic leverage to identify critical principal cell-enriched factors by transcriptional profiling. Elf5, which codes for an ETS transcription factor, is one such gene that is down-regulated in kidneys with Notch-signaling-deficient collecting ducts. Additionally, Elf5 is among the earliest genes up regulated by ectopic expression of activated Notch1 in the developing collecting ducts. In the kidney, Elf5 is first expressed early within developing collecting ducts and remains on in mature principal cells. Lineage tracing of Elf5-expressing cells revealed that they are committed to the principal cell lineage by as early as E16.5. Over-expression of ETS Class IIa transcription factors, including Elf5, Elf3 and Ehf, increase the transcriptional activity of the proximal promoters of Aqp2 and Avpr2 in cultured ureteric duct cell lines. Conditional inactivation of Elf5 in the developing collecting ducts results in a small but significant reduction in the expression levels of Aqp2 and Avpr2 genes. We have identified Elf5 as an early maker of the principal cell lineage that contributes to the expression of principal cell specific genes.
authors.affiliation: Sanford Children's Health Research Center, Sanford Research, 2301 East 60(th) Street North, Sioux Falls, SD 57104, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Grassmeyer
authors.affiliation: Sanford Children's Health Research Center, Sanford Research, 2301 East 60(th) Street North, Sioux Falls, SD 57104, USA.
authors.forename: Malini
authors.initials: M
authors.lastname: Mukherjee
authors.affiliation: Sanford Children's Health Research Center, Sanford Research, 2301 East 60(th) Street North, Sioux Falls, SD 57104, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: deRiso
authors.affiliation: Sanford Children's Health Research Center, Sanford Research, 2301 East 60(th) Street North, Sioux Falls, SD 57104, USA.
authors.forename: Casey
authors.initials: C
authors.lastname: Hettinger
authors.affiliation: Augustana University, Sioux Falls, SD, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Bailey
authors.affiliation: Department of Biochemistry, State University of New York at Buffalo, Center for Excellence in Bioinformatics and Life Sciences, Buffalo, NY 14203, USA.
authors.forename: Satrajit
authors.initials: S
authors.lastname: Sinha
authors.affiliation: Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
authors.forename: Jane E
authors.initials: JE
authors.lastname: Visvader
authors.affiliation: Sanford Children's Health Research Center, Sanford Research, 2301 East 60(th) Street North, Sioux Falls, SD 57104, USA; Department of Pediatrics, Sanford School of Medicine, Sioux Falls, SD 57104, USA.
authors.forename: Haotian
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Sanford Children's Health Research Center, Sanford Research, 2301 East 60(th) Street North, Sioux Falls, SD 57104, USA; Basic Biomedical Sciences graduate program, Sanford School of Medicine of the University of South Dakota, Vermillion, SD 57069 USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Fogarty
authors.affiliation: Sanford Children's Health Research Center, Sanford Research, 2301 East 60(th) Street North, Sioux Falls, SD 57104, USA; Department of Pediatrics, Sanford School of Medicine, Sioux Falls, SD 57104, USA. Electronic address: kameswaran.surendran@sanfordhealth.org.
authors.forename: Kameswaran
authors.initials: K
authors.lastname: Surendran
mesh_terms: D000818:Animals; D051399:Aquaporin 2 / Q000235:genetics* / Q000378:metabolism; D002452:Cell Count; D002460:Cell Line; D019070:Cell Lineage; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000378:metabolism; D019426:Integrases / Q000378:metabolism; D007668:Kidney / Q000166:cytology* / Q000196:embryology / Q000378:metabolism*; D007685:Kidney Tubules, Collecting / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic / Q000235:genetics; D051880:Receptors, Notch / Q000378:metabolism; D017483:Receptors, Vasopressin / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics; D014513:Ureter / Q000196:embryology / Q000378:metabolism
chemical_list: D051399:Aquaporin 2; D004268:DNA-Binding Proteins; C112442:Ehf protein, mouse; C494436:Elf3 protein, mouse; C500759:Elf5 protein, mouse; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; C497571:Rbpj protein, mouse; D051880:Receptors, Notch; D017483:Receptors, Vasopressin; D014157:Transcription Factors; C045073:Cre recombinase; D019426:Integrases
keywords: Collecting ducts; Intercalated cell; Notch; RBPJ; Renal development