Identification of anchor genes during kidney development defines ontological relationships, molecular subcompartments and regulatory pathways

• Published in: PloS one Vol. 6; no. 2; p. e17286
• Main Authors: Thiagarajan, Rathi D, Georgas, Kylie M, Rumballe, Bree A, Lesieur, Emmanuelle, Chiu, Han Sheng, Taylor, Darrin, Tang, Dave T P, Grimmond, Sean M, Little, Melissa H
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 28.02.2011; Public Library of Science (PLoS)
• Subjects: Animals; Binding sites; Biology; Cell Compartmentation - genetics; Cluster Analysis; Collecting duct; Compartments; Data processing; Developmental biology; Diabetes; DNA binding proteins; DNA microarrays; Filtration; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Developmental; Genes; Genes, Developmental - physiology; Genetic research; Genomes; Geospatial data; Hepatocyte nuclear factor 4; Homeostasis; Kidney - embryology; Kidney - metabolism; Kidney diseases; Kidneys; Loop of Henle; Mammals; Mice; Models, Biological; Notch protein; Oligonucleotide Array Sequence Analysis; Ontology; Organogenesis; Organogenesis - genetics; Pattern formation; Retinoid X receptor α; Rodents; Segmentation; Signal transduction; Signal Transduction - genetics; Signal Transduction - physiology; Signaling; Spatial data; Tissue Distribution - genetics; Transcription (Genetics); Transcription factors; Ureter; Validation Studies as Topic; Australia
• DOI: 10.1371/journal.pone.0017286
• ISSN: 1932-6203

The development of the mammalian kidney is well conserved from mouse to man. Despite considerable temporal and spatial data on gene expression in mammalian kidney development, primarily in rodent species, there is a paucity of genes whose expression is absolutely specific to a given anatomical compartment and/or developmental stage, defined here as 'anchor' genes. We previously generated an atlas of gene expression in the developing mouse kidney using microarray analysis of anatomical compartments collected via laser capture microdissection. Here, this data is further analysed to identify anchor genes via stringent bioinformatic filtering followed by high resolution section in situ hybridisation performed on 200 transcripts selected as specific to one of 11 anatomical compartments within the midgestation mouse kidney. A total of 37 anchor genes were identified across 6 compartments with the early proximal tubule being the compartment richest in anchor genes. Analysis of minimal and evolutionarily conserved promoter regions of this set of 25 anchor genes identified enrichment of transcription factor binding sites for Hnf4a and Hnf1b, RbpJ (Notch signalling), PPARγ:RxRA and COUP-TF family transcription factors. This was reinforced by GO analyses which also identified these anchor genes as targets in processes including epithelial proliferation and proximal tubular function. As well as defining anchor genes, this large scale validation of gene expression identified a further 92 compartment-enriched genes able to subcompartmentalise key processes during murine renal organogenesis spatially or ontologically. This included a cohort of 13 ureteric epithelial genes revealing previously unappreciated compartmentalisation of the collecting duct system and a series of early tubule genes suggesting that segmentation into proximal tubule, loop of Henle and distal tubule does not occur until the onset of glomerular vascularisation. Overall, this study serves to illuminate previously ill-defined stages of patterning and will enable further refinement of the lineage relationships within mammalian kidney development.