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

Thiagarajan RD, Georgas KM, Rumballe BA, Lesieur E, Chiu HS, Taylor D, Tang DT, Grimmond SM, Little MH - PLoS ONE (2011)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Australia.

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), PPARĪ³: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.

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Related in: MedlinePlus

Ingenuity/GO analyses of relationships between proximal tubule anchor genes.Functional network analysis of early proximal tubule anchor genes. Network contains gene/gene products represented as nodes and biological relationship between the nodes as edges as curated in the Ingenuity Knowledge Base. Anchor gene nodes (orange) and transcription factors predicted from TF binding site motif analysis (blue) are highlighted. Kidney related functions and disease are represented in white text boxes. Functions directly related to proximal tubule development are outlined in purple, green and red.
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pone-0017286-g006: Ingenuity/GO analyses of relationships between proximal tubule anchor genes.Functional network analysis of early proximal tubule anchor genes. Network contains gene/gene products represented as nodes and biological relationship between the nodes as edges as curated in the Ingenuity Knowledge Base. Anchor gene nodes (orange) and transcription factors predicted from TF binding site motif analysis (blue) are highlighted. Kidney related functions and disease are represented in white text boxes. Functions directly related to proximal tubule development are outlined in purple, green and red.

Mentions: To identify other potential tissue-specific functional networks of proximal tubule, the 25 EPT anchor genes were used for genetic network analysis using Ingenuity Pathway Analysis. Network interactions were inferred using the Ingenuity Knowledge Base of pre-curated molecular and functional interactions mined from published literature. The networks are displayed as nodes (genes) and edges (biological relationships). Networks from 11 genes were merged as one network (Figure 6). This then highlights the direct relationship of genes required for epithelial differentiation to main proximal tubule identity and also proximal tubule function. Many of the genes are also implicated in renal disease, suggesting that a loss of precise regulation of tissue specific genes is detrimental. The analysis also re-identified involvement of several candidate transcription factors, including the previously identified Hnf4a, Hnf1a and members of the PPAR transcription factor family. Other transcription factors identified in this network included Ahr and p53, both of which are known to play a role in kidney development [58], [59]. These networks and pathways highlight the potential importance of maintaining proximal tubular identity where perturbations to these nodes can lead to diseases.


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

Thiagarajan RD, Georgas KM, Rumballe BA, Lesieur E, Chiu HS, Taylor D, Tang DT, Grimmond SM, Little MH - PLoS ONE (2011)

Ingenuity/GO analyses of relationships between proximal tubule anchor genes.Functional network analysis of early proximal tubule anchor genes. Network contains gene/gene products represented as nodes and biological relationship between the nodes as edges as curated in the Ingenuity Knowledge Base. Anchor gene nodes (orange) and transcription factors predicted from TF binding site motif analysis (blue) are highlighted. Kidney related functions and disease are represented in white text boxes. Functions directly related to proximal tubule development are outlined in purple, green and red.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3046260&req=5

pone-0017286-g006: Ingenuity/GO analyses of relationships between proximal tubule anchor genes.Functional network analysis of early proximal tubule anchor genes. Network contains gene/gene products represented as nodes and biological relationship between the nodes as edges as curated in the Ingenuity Knowledge Base. Anchor gene nodes (orange) and transcription factors predicted from TF binding site motif analysis (blue) are highlighted. Kidney related functions and disease are represented in white text boxes. Functions directly related to proximal tubule development are outlined in purple, green and red.
Mentions: To identify other potential tissue-specific functional networks of proximal tubule, the 25 EPT anchor genes were used for genetic network analysis using Ingenuity Pathway Analysis. Network interactions were inferred using the Ingenuity Knowledge Base of pre-curated molecular and functional interactions mined from published literature. The networks are displayed as nodes (genes) and edges (biological relationships). Networks from 11 genes were merged as one network (Figure 6). This then highlights the direct relationship of genes required for epithelial differentiation to main proximal tubule identity and also proximal tubule function. Many of the genes are also implicated in renal disease, suggesting that a loss of precise regulation of tissue specific genes is detrimental. The analysis also re-identified involvement of several candidate transcription factors, including the previously identified Hnf4a, Hnf1a and members of the PPAR transcription factor family. Other transcription factors identified in this network included Ahr and p53, both of which are known to play a role in kidney development [58], [59]. These networks and pathways highlight the potential importance of maintaining proximal tubular identity where perturbations to these nodes can lead to diseases.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Australia.

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), PPARĪ³: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.

Show MeSH
Related in: MedlinePlus