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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.

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Quantitative trait loci (QTL) Heat Map of the top 100 correlates of phosphatase tensin homolog (Pten). The numbers to the left denote the top 100 genes that correlate with Pten and the chromosomal location is noted at the bottom of the heat map ranging from chromosome 1 on the left to chromosome X on the right. The banding pattern is displayed in yellow, red, green, and blue, which denote the locations of the genomic loci that modulate all of the genes in the network. The green (low likelihood ratio statistic; LRS) to blue (high LRS) coloring represents transcripts whose expression is higher in the strains with a B haplotype (C57BL/6J) and the yellow (low LRS) to red (high LRS) coloring corresponds to the transcripts whose expression is higher in the strains with mutant D haplotype (DBA/2J). The red arrows indicate the most prominent bands with significant QTLs and portray the signature bands of the Pten network chromosomes 1, 2, 12, 15, 16, and 19.
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f4: Quantitative trait loci (QTL) Heat Map of the top 100 correlates of phosphatase tensin homolog (Pten). The numbers to the left denote the top 100 genes that correlate with Pten and the chromosomal location is noted at the bottom of the heat map ranging from chromosome 1 on the left to chromosome X on the right. The banding pattern is displayed in yellow, red, green, and blue, which denote the locations of the genomic loci that modulate all of the genes in the network. The green (low likelihood ratio statistic; LRS) to blue (high LRS) coloring represents transcripts whose expression is higher in the strains with a B haplotype (C57BL/6J) and the yellow (low LRS) to red (high LRS) coloring corresponds to the transcripts whose expression is higher in the strains with mutant D haplotype (DBA/2J). The red arrows indicate the most prominent bands with significant QTLs and portray the signature bands of the Pten network chromosomes 1, 2, 12, 15, 16, and 19.

Mentions: Our initial analysis displayed the Gap43 signature as a cohort of transcripts co-regulated by the signature QTLs in the retinal ganglion cells. Gap43 is of particular interest to our laboratory because of the Gap43 association with growing axons and abortive regeneration in the retina [28,29]. When we examined the list of genes that correlate with the expression pattern of Gap43 across the BXD RI strain set, Pten was discovered to have a relatively high correlation of 0.63 and has a similar expression pattern across the BXD RI strains. The high correlation is interesting because both genes, Gap43 and Pten, are expressed in the retinal ganglion cells and Pten has been reported to be involved in axonal regeneration [30,31]. We hypothesize that Pten may share similar modulating QTLs to Gap43. Additionally, Gap43 and Pten may participate within one molecular pathway in the retinal ganglion cells. Similar with the Gap43 signature, the Pten signature displays QTLs on chromosomes 1, 2, 12, 15, 16, and 19 (Figure 4), which suggests that Gap43 is co-regulated with Pten within the same genetic network of the retinal ganglion cells. This network shares a series of signature QTLs that may modulate the response of the ganglion cells to axonal injury: either abortive regeneration [32] or potentially axonal regeneration [30,31]. With further investigation of this network, it may be possible to define genes that act as modulators of both Gap43 and Pten. For example, when the top 2,000 correlates of Gap43 and Pten are compared (see Appendix 3), 1,109 genes are found to be in common, which indicates that Gap43 and Pten participate within a single genetic network.


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)

Quantitative trait loci (QTL) Heat Map of the top 100 correlates of phosphatase tensin homolog (Pten). The numbers to the left denote the top 100 genes that correlate with Pten and the chromosomal location is noted at the bottom of the heat map ranging from chromosome 1 on the left to chromosome X on the right. The banding pattern is displayed in yellow, red, green, and blue, which denote the locations of the genomic loci that modulate all of the genes in the network. The green (low likelihood ratio statistic; LRS) to blue (high LRS) coloring represents transcripts whose expression is higher in the strains with a B haplotype (C57BL/6J) and the yellow (low LRS) to red (high LRS) coloring corresponds to the transcripts whose expression is higher in the strains with mutant D haplotype (DBA/2J). The red arrows indicate the most prominent bands with significant QTLs and portray the signature bands of the Pten network chromosomes 1, 2, 12, 15, 16, and 19.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f4: Quantitative trait loci (QTL) Heat Map of the top 100 correlates of phosphatase tensin homolog (Pten). The numbers to the left denote the top 100 genes that correlate with Pten and the chromosomal location is noted at the bottom of the heat map ranging from chromosome 1 on the left to chromosome X on the right. The banding pattern is displayed in yellow, red, green, and blue, which denote the locations of the genomic loci that modulate all of the genes in the network. The green (low likelihood ratio statistic; LRS) to blue (high LRS) coloring represents transcripts whose expression is higher in the strains with a B haplotype (C57BL/6J) and the yellow (low LRS) to red (high LRS) coloring corresponds to the transcripts whose expression is higher in the strains with mutant D haplotype (DBA/2J). The red arrows indicate the most prominent bands with significant QTLs and portray the signature bands of the Pten network chromosomes 1, 2, 12, 15, 16, and 19.
Mentions: Our initial analysis displayed the Gap43 signature as a cohort of transcripts co-regulated by the signature QTLs in the retinal ganglion cells. Gap43 is of particular interest to our laboratory because of the Gap43 association with growing axons and abortive regeneration in the retina [28,29]. When we examined the list of genes that correlate with the expression pattern of Gap43 across the BXD RI strain set, Pten was discovered to have a relatively high correlation of 0.63 and has a similar expression pattern across the BXD RI strains. The high correlation is interesting because both genes, Gap43 and Pten, are expressed in the retinal ganglion cells and Pten has been reported to be involved in axonal regeneration [30,31]. We hypothesize that Pten may share similar modulating QTLs to Gap43. Additionally, Gap43 and Pten may participate within one molecular pathway in the retinal ganglion cells. Similar with the Gap43 signature, the Pten signature displays QTLs on chromosomes 1, 2, 12, 15, 16, and 19 (Figure 4), which suggests that Gap43 is co-regulated with Pten within the same genetic network of the retinal ganglion cells. This network shares a series of signature QTLs that may modulate the response of the ganglion cells to axonal injury: either abortive regeneration [32] or potentially axonal regeneration [30,31]. With further investigation of this network, it may be possible to define genes that act as modulators of both Gap43 and Pten. For example, when the top 2,000 correlates of Gap43 and Pten are compared (see Appendix 3), 1,109 genes are found to be in common, which indicates that Gap43 and Pten participate within a single genetic network.

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