Abstract

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.

Highlights

  • Many diseases of the kidney stem from disruptions to the transcriptional programs involved in normal kidney development [1]

  • In the study presented here, we have extended the analysis of the kidney development gene atlas using high resolution section in situ hybridisation (SISH)

  • Selecting potential anchor genes via reanalysis of the atlas of kidney development Brunskill et al (2008) [25] reported Affymetrix expression profiling for 15 compartments, 11 of which were isolated from embryonic day (E) 15.5 developing murine kidney

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Summary

Introduction

Many diseases of the kidney stem from disruptions to the transcriptional programs involved in normal kidney development [1]. Compartment-enriched genes redefined the developing kidney atlas into molecular events rather than regional or anatomical structures, identifying markers able to subdivide the processes of nephron segmentation, collecting duct functionalisation and interstitial differentiation.

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