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Conserved genes act as modifiers of invertebrate SMN loss of function defects.

Dimitriadi M, Sleigh JN, Walker A, Chang HC, Sen A, Kalloo G, Harris J, Barsby T, Walsh MB, Satterlee JS, Li C, Van Vactor D, Artavanis-Tsakonas S, Hart AC - PLoS Genet. (2010)

Bottom Line: Second, we tested the conservation of modifier gene function across species; genes identified in one invertebrate model were tested for function in the other invertebrate model.Drosophila orthologs of two genes, which were identified originally in C. elegans, modified Drosophila SMN loss of function defects.Bioinformatic analysis of the conserved, cross-species, modifier genes suggests that conserved cellular pathways, specifically endocytosis and mRNA regulation, act as critical genetic modifiers of SMN loss of function defects across species.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, Brown University, Providence, Rhode Island, USA.

ABSTRACT
Spinal Muscular Atrophy (SMA) is caused by diminished function of the Survival of Motor Neuron (SMN) protein, but the molecular pathways critical for SMA pathology remain elusive. We have used genetic approaches in invertebrate models to identify conserved SMN loss of function modifier genes. Drosophila melanogaster and Caenorhabditis elegans each have a single gene encoding a protein orthologous to human SMN; diminished function of these invertebrate genes causes lethality and neuromuscular defects. To find genes that modulate SMN function defects across species, two approaches were used. First, a genome-wide RNAi screen for C. elegans SMN modifier genes was undertaken, yielding four genes. Second, we tested the conservation of modifier gene function across species; genes identified in one invertebrate model were tested for function in the other invertebrate model. Drosophila orthologs of two genes, which were identified originally in C. elegans, modified Drosophila SMN loss of function defects. C. elegans orthologs of twelve genes, which were originally identified in a previous Drosophila screen, modified C. elegans SMN loss of function defects. Bioinformatic analysis of the conserved, cross-species, modifier genes suggests that conserved cellular pathways, specifically endocytosis and mRNA regulation, act as critical genetic modifiers of SMN loss of function defects across species.

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Interaction map of SMN modifier genes.A) Numerous published physical and/or functional interactions were found in the literature that connect many invertebrate SMN modifier genes. The names of vertebrate genes are used in the figure, but interactions are drawn from literature in any animal species. Each type of interaction is represented by different colors of connecting lines and references are provided in the table in part B. Not all interactions are indicated including interactions of FGF, TGF-beta and neuropeptide signaling pathways with endocytosis/cytoskeletal pathways, dynein interactions with APP [101] and possible connection between VAPB, the ALS8 locus, and SK channels through riluzole [102]–[106]. The interaction analysis here is not exhaustive and additional interactions may exist. B) The type of interaction is indicated in the table [107]–[155]: P pull-down, Y yeast 2-hybrid, F functional/genetic, D direct physical interaction. Genes shaded in blue are cross-species invertebrate modifiers; genes shaded in yellow are mammalian genes whose perturbation can cause neurodegeneration; genes outlined in grey are SMA modifiers in drug studies or in patients. Genes pertinent to endocytosis include CIN85, EndoA, Alix, PLS3, CAV1, GPRK, Ataxin2, Profilin, EPS15, Phocein, Dynamin, and Striatin; genes pertinent to RNA processing include PABP, CBC20, DcpS, SMN, and FMRP. Combined, our results and published studies support a model in which endocytosis and RNA translational control pathways are physically and functionally coupled [92], [93]. In normal animals, coupling of these seemingly disparate pathways may help coordinate synaptic activity and protein synthesis in the neuromuscular system.
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pgen-1001172-g007: Interaction map of SMN modifier genes.A) Numerous published physical and/or functional interactions were found in the literature that connect many invertebrate SMN modifier genes. The names of vertebrate genes are used in the figure, but interactions are drawn from literature in any animal species. Each type of interaction is represented by different colors of connecting lines and references are provided in the table in part B. Not all interactions are indicated including interactions of FGF, TGF-beta and neuropeptide signaling pathways with endocytosis/cytoskeletal pathways, dynein interactions with APP [101] and possible connection between VAPB, the ALS8 locus, and SK channels through riluzole [102]–[106]. The interaction analysis here is not exhaustive and additional interactions may exist. B) The type of interaction is indicated in the table [107]–[155]: P pull-down, Y yeast 2-hybrid, F functional/genetic, D direct physical interaction. Genes shaded in blue are cross-species invertebrate modifiers; genes shaded in yellow are mammalian genes whose perturbation can cause neurodegeneration; genes outlined in grey are SMA modifiers in drug studies or in patients. Genes pertinent to endocytosis include CIN85, EndoA, Alix, PLS3, CAV1, GPRK, Ataxin2, Profilin, EPS15, Phocein, Dynamin, and Striatin; genes pertinent to RNA processing include PABP, CBC20, DcpS, SMN, and FMRP. Combined, our results and published studies support a model in which endocytosis and RNA translational control pathways are physically and functionally coupled [92], [93]. In normal animals, coupling of these seemingly disparate pathways may help coordinate synaptic activity and protein synthesis in the neuromuscular system.

Mentions: Combined the results described here define eleven conserved genes that modify invertebrate SMN ortholog function in at least one assay in both C. elegans and Drosophila (summarized in Table 4). A subset of these cross-species modifier genes interact, directly or indirectly, with previously described neurological or neuromuscular disease proteins suggesting common neurodegenerative pathways may be at work (i.e. ATF6 with VAPB/ALS8 or GPRK2 and SMN1 with FMRP) [75]–[77]. To determine if specific cellular mechanisms could be implicated in SMN loss of function pathology, the published literature and public databases were examined for physical and/or functional interactions between cross-species SMN modifier genes, SMN and neuromuscular disease genes. A protein/genetic interaction map was assembled and is presented in Figure 7 with references. We note that genes implicated in endocytosis and mRNA translational regulation unexpectedly predominate in this interaction map. These two cellular pathways may be pertinent to SMN loss of function pathology.


Conserved genes act as modifiers of invertebrate SMN loss of function defects.

Dimitriadi M, Sleigh JN, Walker A, Chang HC, Sen A, Kalloo G, Harris J, Barsby T, Walsh MB, Satterlee JS, Li C, Van Vactor D, Artavanis-Tsakonas S, Hart AC - PLoS Genet. (2010)

Interaction map of SMN modifier genes.A) Numerous published physical and/or functional interactions were found in the literature that connect many invertebrate SMN modifier genes. The names of vertebrate genes are used in the figure, but interactions are drawn from literature in any animal species. Each type of interaction is represented by different colors of connecting lines and references are provided in the table in part B. Not all interactions are indicated including interactions of FGF, TGF-beta and neuropeptide signaling pathways with endocytosis/cytoskeletal pathways, dynein interactions with APP [101] and possible connection between VAPB, the ALS8 locus, and SK channels through riluzole [102]–[106]. The interaction analysis here is not exhaustive and additional interactions may exist. B) The type of interaction is indicated in the table [107]–[155]: P pull-down, Y yeast 2-hybrid, F functional/genetic, D direct physical interaction. Genes shaded in blue are cross-species invertebrate modifiers; genes shaded in yellow are mammalian genes whose perturbation can cause neurodegeneration; genes outlined in grey are SMA modifiers in drug studies or in patients. Genes pertinent to endocytosis include CIN85, EndoA, Alix, PLS3, CAV1, GPRK, Ataxin2, Profilin, EPS15, Phocein, Dynamin, and Striatin; genes pertinent to RNA processing include PABP, CBC20, DcpS, SMN, and FMRP. Combined, our results and published studies support a model in which endocytosis and RNA translational control pathways are physically and functionally coupled [92], [93]. In normal animals, coupling of these seemingly disparate pathways may help coordinate synaptic activity and protein synthesis in the neuromuscular system.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2965752&req=5

pgen-1001172-g007: Interaction map of SMN modifier genes.A) Numerous published physical and/or functional interactions were found in the literature that connect many invertebrate SMN modifier genes. The names of vertebrate genes are used in the figure, but interactions are drawn from literature in any animal species. Each type of interaction is represented by different colors of connecting lines and references are provided in the table in part B. Not all interactions are indicated including interactions of FGF, TGF-beta and neuropeptide signaling pathways with endocytosis/cytoskeletal pathways, dynein interactions with APP [101] and possible connection between VAPB, the ALS8 locus, and SK channels through riluzole [102]–[106]. The interaction analysis here is not exhaustive and additional interactions may exist. B) The type of interaction is indicated in the table [107]–[155]: P pull-down, Y yeast 2-hybrid, F functional/genetic, D direct physical interaction. Genes shaded in blue are cross-species invertebrate modifiers; genes shaded in yellow are mammalian genes whose perturbation can cause neurodegeneration; genes outlined in grey are SMA modifiers in drug studies or in patients. Genes pertinent to endocytosis include CIN85, EndoA, Alix, PLS3, CAV1, GPRK, Ataxin2, Profilin, EPS15, Phocein, Dynamin, and Striatin; genes pertinent to RNA processing include PABP, CBC20, DcpS, SMN, and FMRP. Combined, our results and published studies support a model in which endocytosis and RNA translational control pathways are physically and functionally coupled [92], [93]. In normal animals, coupling of these seemingly disparate pathways may help coordinate synaptic activity and protein synthesis in the neuromuscular system.
Mentions: Combined the results described here define eleven conserved genes that modify invertebrate SMN ortholog function in at least one assay in both C. elegans and Drosophila (summarized in Table 4). A subset of these cross-species modifier genes interact, directly or indirectly, with previously described neurological or neuromuscular disease proteins suggesting common neurodegenerative pathways may be at work (i.e. ATF6 with VAPB/ALS8 or GPRK2 and SMN1 with FMRP) [75]–[77]. To determine if specific cellular mechanisms could be implicated in SMN loss of function pathology, the published literature and public databases were examined for physical and/or functional interactions between cross-species SMN modifier genes, SMN and neuromuscular disease genes. A protein/genetic interaction map was assembled and is presented in Figure 7 with references. We note that genes implicated in endocytosis and mRNA translational regulation unexpectedly predominate in this interaction map. These two cellular pathways may be pertinent to SMN loss of function pathology.

Bottom Line: Second, we tested the conservation of modifier gene function across species; genes identified in one invertebrate model were tested for function in the other invertebrate model.Drosophila orthologs of two genes, which were identified originally in C. elegans, modified Drosophila SMN loss of function defects.Bioinformatic analysis of the conserved, cross-species, modifier genes suggests that conserved cellular pathways, specifically endocytosis and mRNA regulation, act as critical genetic modifiers of SMN loss of function defects across species.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, Brown University, Providence, Rhode Island, USA.

ABSTRACT
Spinal Muscular Atrophy (SMA) is caused by diminished function of the Survival of Motor Neuron (SMN) protein, but the molecular pathways critical for SMA pathology remain elusive. We have used genetic approaches in invertebrate models to identify conserved SMN loss of function modifier genes. Drosophila melanogaster and Caenorhabditis elegans each have a single gene encoding a protein orthologous to human SMN; diminished function of these invertebrate genes causes lethality and neuromuscular defects. To find genes that modulate SMN function defects across species, two approaches were used. First, a genome-wide RNAi screen for C. elegans SMN modifier genes was undertaken, yielding four genes. Second, we tested the conservation of modifier gene function across species; genes identified in one invertebrate model were tested for function in the other invertebrate model. Drosophila orthologs of two genes, which were identified originally in C. elegans, modified Drosophila SMN loss of function defects. C. elegans orthologs of twelve genes, which were originally identified in a previous Drosophila screen, modified C. elegans SMN loss of function defects. Bioinformatic analysis of the conserved, cross-species, modifier genes suggests that conserved cellular pathways, specifically endocytosis and mRNA regulation, act as critical genetic modifiers of SMN loss of function defects across species.

Show MeSH
Related in: MedlinePlus