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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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Related in: MedlinePlus

The cellular signatures of growth associated protein 43 (Gap43), retinal pigment epithelium-specific protein 65 kDa (Rpe65), and choline O-acetyltransferase (Chat) illustrated by quantitative trait loci (QTL) heat maps. The correlation matrices within GeneNetwork were used to simultaneous map and analyze the top 80 genes in the trait collections of A: Gap43, B: Rpe65, and C: Chat. The gene collections from Gap43, Rpe65, and Chat form unique signatures within the retina transcriptome. The numbers to the left denote the correlation range and at the bottom of the heat maps the chromosomal location is noted 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 hues: yellow, red, green, and blue represent significant QTLs. The green (low 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 that some of the bands are more prominent. Running a QTL cluster map in GeneNetwork reveals a strong QTL signature of Gap43, forming a potential genetic network. Signature QTLs (highlighted with red arrows) for Gap43 were found on chromosomes 1, 2, 7, 12, 15, 16, and 19. These are regions of the genome that contain loci modulating the expression of genes within the Gap43 network (A). Rpe65 forms signature QTLs on chromosomes 1, 9, and 16 (B) and Chat forms signature QTLs on chromosomes 1, 5, 7, and 9 (C).
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f3: The cellular signatures of growth associated protein 43 (Gap43), retinal pigment epithelium-specific protein 65 kDa (Rpe65), and choline O-acetyltransferase (Chat) illustrated by quantitative trait loci (QTL) heat maps. The correlation matrices within GeneNetwork were used to simultaneous map and analyze the top 80 genes in the trait collections of A: Gap43, B: Rpe65, and C: Chat. The gene collections from Gap43, Rpe65, and Chat form unique signatures within the retina transcriptome. The numbers to the left denote the correlation range and at the bottom of the heat maps the chromosomal location is noted 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 hues: yellow, red, green, and blue represent significant QTLs. The green (low 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 that some of the bands are more prominent. Running a QTL cluster map in GeneNetwork reveals a strong QTL signature of Gap43, forming a potential genetic network. Signature QTLs (highlighted with red arrows) for Gap43 were found on chromosomes 1, 2, 7, 12, 15, 16, and 19. These are regions of the genome that contain loci modulating the expression of genes within the Gap43 network (A). Rpe65 forms signature QTLs on chromosomes 1, 9, and 16 (B) and Chat forms signature QTLs on chromosomes 1, 5, 7, and 9 (C).

Mentions: The cellular signature of the genes that are uniquely expressed within specific retinal cell types can be identified within the HEI Retina Database; however, this does not mean that within a single cell type there is only one network. In fact, all cells will have multiple genetic networks that regulate specific cellular functions. A list of cell signature genes is presented in Table 1. For each of the cell signature genes listed in Table 1, GeneNetwork can be used to create a list of genes whose expression levels are highly correlated and form a unique signature of the expression pattern(s) within the specific cell type. For example, Gap43 forms a retinal ganglion cell signature, and within the top 100 correlates of Gap43 (see Appendix 2) we find genes such as G protein-coupled receptor 85 (Gpr85), Janus kinase1 (Jak1), heat shock protein 1 chaperonin 10 (Hspe1), neuron specific gene family member (Nsg1), translin (Tsn), beta helix-loop-helix domain containing, class B5 (Bhlhb5), cytochrome c, somatic (Cycs), and beclin 1, autophagy related (Becn1). The top 100 correlates of Gap43 are a highly correlated list of genes with the 99th and 100th gene (male specific lethal-2 homolog1 [Msl2l1] and family with sequence similarity 108, member C [Fam108c, RIKEN clone]) having a correlation of r=0.79. The QTL heat map for Gap43 (Figure 3A) reveals a unique set of genomic loci that regulate this list of genes while displaying a unique signature pattern of the genomic loci that modulate the genes expressed in retinal ganglion cells. The collection of genes forming these dense bands are termed signature QTLs [13]. Signature QTLs are genetic networks with a unique set of genomic loci that co-vary with the trait Gap43. Each band represents a region of the genome that modulates the collections of genes that are co-regulated within the specific cell type.


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 cellular signatures of growth associated protein 43 (Gap43), retinal pigment epithelium-specific protein 65 kDa (Rpe65), and choline O-acetyltransferase (Chat) illustrated by quantitative trait loci (QTL) heat maps. The correlation matrices within GeneNetwork were used to simultaneous map and analyze the top 80 genes in the trait collections of A: Gap43, B: Rpe65, and C: Chat. The gene collections from Gap43, Rpe65, and Chat form unique signatures within the retina transcriptome. The numbers to the left denote the correlation range and at the bottom of the heat maps the chromosomal location is noted 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 hues: yellow, red, green, and blue represent significant QTLs. The green (low 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 that some of the bands are more prominent. Running a QTL cluster map in GeneNetwork reveals a strong QTL signature of Gap43, forming a potential genetic network. Signature QTLs (highlighted with red arrows) for Gap43 were found on chromosomes 1, 2, 7, 12, 15, 16, and 19. These are regions of the genome that contain loci modulating the expression of genes within the Gap43 network (A). Rpe65 forms signature QTLs on chromosomes 1, 9, and 16 (B) and Chat forms signature QTLs on chromosomes 1, 5, 7, and 9 (C).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f3: The cellular signatures of growth associated protein 43 (Gap43), retinal pigment epithelium-specific protein 65 kDa (Rpe65), and choline O-acetyltransferase (Chat) illustrated by quantitative trait loci (QTL) heat maps. The correlation matrices within GeneNetwork were used to simultaneous map and analyze the top 80 genes in the trait collections of A: Gap43, B: Rpe65, and C: Chat. The gene collections from Gap43, Rpe65, and Chat form unique signatures within the retina transcriptome. The numbers to the left denote the correlation range and at the bottom of the heat maps the chromosomal location is noted 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 hues: yellow, red, green, and blue represent significant QTLs. The green (low 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 that some of the bands are more prominent. Running a QTL cluster map in GeneNetwork reveals a strong QTL signature of Gap43, forming a potential genetic network. Signature QTLs (highlighted with red arrows) for Gap43 were found on chromosomes 1, 2, 7, 12, 15, 16, and 19. These are regions of the genome that contain loci modulating the expression of genes within the Gap43 network (A). Rpe65 forms signature QTLs on chromosomes 1, 9, and 16 (B) and Chat forms signature QTLs on chromosomes 1, 5, 7, and 9 (C).
Mentions: The cellular signature of the genes that are uniquely expressed within specific retinal cell types can be identified within the HEI Retina Database; however, this does not mean that within a single cell type there is only one network. In fact, all cells will have multiple genetic networks that regulate specific cellular functions. A list of cell signature genes is presented in Table 1. For each of the cell signature genes listed in Table 1, GeneNetwork can be used to create a list of genes whose expression levels are highly correlated and form a unique signature of the expression pattern(s) within the specific cell type. For example, Gap43 forms a retinal ganglion cell signature, and within the top 100 correlates of Gap43 (see Appendix 2) we find genes such as G protein-coupled receptor 85 (Gpr85), Janus kinase1 (Jak1), heat shock protein 1 chaperonin 10 (Hspe1), neuron specific gene family member (Nsg1), translin (Tsn), beta helix-loop-helix domain containing, class B5 (Bhlhb5), cytochrome c, somatic (Cycs), and beclin 1, autophagy related (Becn1). The top 100 correlates of Gap43 are a highly correlated list of genes with the 99th and 100th gene (male specific lethal-2 homolog1 [Msl2l1] and family with sequence similarity 108, member C [Fam108c, RIKEN clone]) having a correlation of r=0.79. The QTL heat map for Gap43 (Figure 3A) reveals a unique set of genomic loci that regulate this list of genes while displaying a unique signature pattern of the genomic loci that modulate the genes expressed in retinal ganglion cells. The collection of genes forming these dense bands are termed signature QTLs [13]. Signature QTLs are genetic networks with a unique set of genomic loci that co-vary with the trait Gap43. Each band represents a region of the genome that modulates the collections of genes that are co-regulated within the specific cell type.

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