Limits...
Genetic networks in the mouse retina: growth associated protein 43 and phosphatase tensin homolog network.

Freeman NE, Templeton JP, Orr WE, Lu L, Williams RW, Geisert EE - Mol. Vis. (2011)

Bottom Line: For example, we define the genetic network regulating growth associated protein 43 (Gap43) and phosphatase tensin homolog (Pten).Two genes associated with axonal outgrowth (Gap43 and Pten) were used to display the power of this new retina database.The Gap43 and Pten network highlights the covariance of gene expression and forms a molecular network associated with axonal outgrowth in the adult retina.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology and Center for Vision Research, Memphis, TN, USA.

ABSTRACT

Purpose: The present study examines the structure and covariance of endogenous variation in gene expression across the recently expanded family of C57BL/6J (B) X DBA/2J (D) Recombinant Inbred (BXD RI) strains of mice. This work is accompanied by a highly interactive database that can be used to generate and test specific hypotheses. For example, we define the genetic network regulating growth associated protein 43 (Gap43) and phosphatase tensin homolog (Pten).

Methods: The Hamilton Eye Institute (HEI) Retina Database within GeneNetwork features the data analysis of 346 Illumina Sentrix BeadChip Arrays (mouse whole genome-6 version 2). Eighty strains of mice are presented, including 75 BXD RI strains, the parental strains (C57BL/6J and DBA/2J), the reciprocal crosses, and the BALB/cByJ mice. Independent biologic samples for at least two animals from each gender were obtained with a narrow age range (48 to 118 days). Total RNA was prepared followed by the production of biotinylated cRNAs, which were pipetted into the Mouse WG-6V2 arrays. The data was globally normalized with rank invariant and stabilization (2z+8).

Results: The HEI Retina Database is located on the GeneNetwork website. The database was used to extract unique transcriptome signatures for specific cell types in the retina (retinal pigment epithelial, amacrine, and retinal ganglion cells). Two genes associated with axonal outgrowth (Gap43 and Pten) were used to display the power of this new retina database. Bioinformatic tools located within GeneNetwork in conjunction with the HEI Retina Database were used to identify the unique signature Quantitative Trait Loci (QTLs) for Gap43 and Pten on chromosomes 1, 2, 12, 15, 16, and 19. Gap43 and Pten possess networks that are similar to ganglion cell networks that may be associated with axonal growth in the mouse retina. This network involves high correlations of transcription factors (SRY sex determining region Y-box 2 [Sox2], paired box gene 6 [Pax6], and neurogenic differentiation 1 [Neurod1]), and genes involved in DNA binding (proliferating cell nuclear antigen [Pcna] and zinc finger, BED-type containing 4 [Zbed4]), as well as an inhibitor of DNA binding (inhibitor of DNA binding 2, dominant negative helix-loop-helix protein [Id2]). Furthermore, we identified the potential upstream modifiers on chromosome 2 (teashirt zinc finger homeobox 2 [Tshz2], RNA export 1 homolog [Rae1] and basic helix-loop-helix domain contatining, class B4 [Bhlhb4]) on chromosome 15 (RAB, member of RAS oncogene family-like 2a [Rabl2a], phosphomannomutase 1 [Pmm1], copine VIII [Cpne8], and fibulin 1 [Fbln1]).

Conclusions: The endogenous variation in mRNA levels among BXD RI strains can be used to explore and test expression networks underlying variation in retina structure, function, and disease susceptibility. The Gap43 and Pten network highlights the covariance of gene expression and forms a molecular network associated with axonal outgrowth in the adult retina.

Show MeSH

Related in: MedlinePlus

The Hamilton Eye Institute (HEI) Retina Database and GeneNetwork can reveal the covariance in gene expression that establishes genetic networks in the retina. A: Input: A systems biology approach and the microarray data from 75 BXD RI mouse retinas feed into the HEI Retina Database. B: Databases: The HEI Retina Database links to the interactive GeneNetwork Database website. C: Analysis: The analytical tools within GeneNetwork are used to interrogate the data set and detect the co-variance among sets of genes that map to a common genetic locus and collectively control a complex trait. D: Outcomes: Identify the unique genomic loci that co-vary with the trait of interest, which lends to the discovery of quantitative trait loci (QTL), cellular, and tissue signatures. These signatures allow the construction of schema for genetic networks.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3108897&req=5

f1: The Hamilton Eye Institute (HEI) Retina Database and GeneNetwork can reveal the covariance in gene expression that establishes genetic networks in the retina. A: Input: A systems biology approach and the microarray data from 75 BXD RI mouse retinas feed into the HEI Retina Database. B: Databases: The HEI Retina Database links to the interactive GeneNetwork Database website. C: Analysis: The analytical tools within GeneNetwork are used to interrogate the data set and detect the co-variance among sets of genes that map to a common genetic locus and collectively control a complex trait. D: Outcomes: Identify the unique genomic loci that co-vary with the trait of interest, which lends to the discovery of quantitative trait loci (QTL), cellular, and tissue signatures. These signatures allow the construction of schema for genetic networks.

Mentions: The second component—the systems biology approach—takes advantage of high throughput expression profiling of the entire family of strains. The expression data from 80 strains and both sexes would be overwhelming without special analytic tools, and for that reason we have integrated the entire data set in GeneNetwork for rapid online analysis. In Figure 1, we illustrate the process of exploiting natural perturbations of gene expression to define specific molecular networks in retina. We provide one example that highlights a network associated with axonal outgrowth in the adult mouse retina. This network is defined in part by high natural covariance among transcription factors: SRY (sex determining region Y)-box 2 [Sox2] and paired box gene 6 [Pax6], neurogenic differentiation 1 [Neurod1]), genes involved in axonal outgrowth (growth associated protein 43 [Gap43] and phosphatase tensin homolog [Pten]), genes involved in DNA binding (proliferating cell nuclear antigen [Pcna] and zinc finger, BED-type containing 4 [Zbed4]), and an inhibitor of DNA binding [inhibitor of DNA binding 2, dominant negative helix–loop–helix protein [Id2]). The use of a systems genetics approach that exploits large expression data sets for entire families of strains with online resources provides a powerful and practical way to study and test the genetics of retinal function and disease susceptibility.


Genetic networks in the mouse retina: growth associated protein 43 and phosphatase tensin homolog network.

Freeman NE, Templeton JP, Orr WE, Lu L, Williams RW, Geisert EE - Mol. Vis. (2011)

The Hamilton Eye Institute (HEI) Retina Database and GeneNetwork can reveal the covariance in gene expression that establishes genetic networks in the retina. A: Input: A systems biology approach and the microarray data from 75 BXD RI mouse retinas feed into the HEI Retina Database. B: Databases: The HEI Retina Database links to the interactive GeneNetwork Database website. C: Analysis: The analytical tools within GeneNetwork are used to interrogate the data set and detect the co-variance among sets of genes that map to a common genetic locus and collectively control a complex trait. D: Outcomes: Identify the unique genomic loci that co-vary with the trait of interest, which lends to the discovery of quantitative trait loci (QTL), cellular, and tissue signatures. These signatures allow the construction of schema for genetic networks.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3108897&req=5

f1: The Hamilton Eye Institute (HEI) Retina Database and GeneNetwork can reveal the covariance in gene expression that establishes genetic networks in the retina. A: Input: A systems biology approach and the microarray data from 75 BXD RI mouse retinas feed into the HEI Retina Database. B: Databases: The HEI Retina Database links to the interactive GeneNetwork Database website. C: Analysis: The analytical tools within GeneNetwork are used to interrogate the data set and detect the co-variance among sets of genes that map to a common genetic locus and collectively control a complex trait. D: Outcomes: Identify the unique genomic loci that co-vary with the trait of interest, which lends to the discovery of quantitative trait loci (QTL), cellular, and tissue signatures. These signatures allow the construction of schema for genetic networks.
Mentions: The second component—the systems biology approach—takes advantage of high throughput expression profiling of the entire family of strains. The expression data from 80 strains and both sexes would be overwhelming without special analytic tools, and for that reason we have integrated the entire data set in GeneNetwork for rapid online analysis. In Figure 1, we illustrate the process of exploiting natural perturbations of gene expression to define specific molecular networks in retina. We provide one example that highlights a network associated with axonal outgrowth in the adult mouse retina. This network is defined in part by high natural covariance among transcription factors: SRY (sex determining region Y)-box 2 [Sox2] and paired box gene 6 [Pax6], neurogenic differentiation 1 [Neurod1]), genes involved in axonal outgrowth (growth associated protein 43 [Gap43] and phosphatase tensin homolog [Pten]), genes involved in DNA binding (proliferating cell nuclear antigen [Pcna] and zinc finger, BED-type containing 4 [Zbed4]), and an inhibitor of DNA binding [inhibitor of DNA binding 2, dominant negative helix–loop–helix protein [Id2]). The use of a systems genetics approach that exploits large expression data sets for entire families of strains with online resources provides a powerful and practical way to study and test the genetics of retinal function and disease susceptibility.

Bottom Line: For example, we define the genetic network regulating growth associated protein 43 (Gap43) and phosphatase tensin homolog (Pten).Two genes associated with axonal outgrowth (Gap43 and Pten) were used to display the power of this new retina database.The Gap43 and Pten network highlights the covariance of gene expression and forms a molecular network associated with axonal outgrowth in the adult retina.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology and Center for Vision Research, Memphis, TN, USA.

ABSTRACT

Purpose: The present study examines the structure and covariance of endogenous variation in gene expression across the recently expanded family of C57BL/6J (B) X DBA/2J (D) Recombinant Inbred (BXD RI) strains of mice. This work is accompanied by a highly interactive database that can be used to generate and test specific hypotheses. For example, we define the genetic network regulating growth associated protein 43 (Gap43) and phosphatase tensin homolog (Pten).

Methods: The Hamilton Eye Institute (HEI) Retina Database within GeneNetwork features the data analysis of 346 Illumina Sentrix BeadChip Arrays (mouse whole genome-6 version 2). Eighty strains of mice are presented, including 75 BXD RI strains, the parental strains (C57BL/6J and DBA/2J), the reciprocal crosses, and the BALB/cByJ mice. Independent biologic samples for at least two animals from each gender were obtained with a narrow age range (48 to 118 days). Total RNA was prepared followed by the production of biotinylated cRNAs, which were pipetted into the Mouse WG-6V2 arrays. The data was globally normalized with rank invariant and stabilization (2z+8).

Results: The HEI Retina Database is located on the GeneNetwork website. The database was used to extract unique transcriptome signatures for specific cell types in the retina (retinal pigment epithelial, amacrine, and retinal ganglion cells). Two genes associated with axonal outgrowth (Gap43 and Pten) were used to display the power of this new retina database. Bioinformatic tools located within GeneNetwork in conjunction with the HEI Retina Database were used to identify the unique signature Quantitative Trait Loci (QTLs) for Gap43 and Pten on chromosomes 1, 2, 12, 15, 16, and 19. Gap43 and Pten possess networks that are similar to ganglion cell networks that may be associated with axonal growth in the mouse retina. This network involves high correlations of transcription factors (SRY sex determining region Y-box 2 [Sox2], paired box gene 6 [Pax6], and neurogenic differentiation 1 [Neurod1]), and genes involved in DNA binding (proliferating cell nuclear antigen [Pcna] and zinc finger, BED-type containing 4 [Zbed4]), as well as an inhibitor of DNA binding (inhibitor of DNA binding 2, dominant negative helix-loop-helix protein [Id2]). Furthermore, we identified the potential upstream modifiers on chromosome 2 (teashirt zinc finger homeobox 2 [Tshz2], RNA export 1 homolog [Rae1] and basic helix-loop-helix domain contatining, class B4 [Bhlhb4]) on chromosome 15 (RAB, member of RAS oncogene family-like 2a [Rabl2a], phosphomannomutase 1 [Pmm1], copine VIII [Cpne8], and fibulin 1 [Fbln1]).

Conclusions: The endogenous variation in mRNA levels among BXD RI strains can be used to explore and test expression networks underlying variation in retina structure, function, and disease susceptibility. The Gap43 and Pten network highlights the covariance of gene expression and forms a molecular network associated with axonal outgrowth in the adult retina.

Show MeSH
Related in: MedlinePlus