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Major signaling pathways in migrating neuroblasts.

Khodosevich K, Seeburg PH, Monyer H - Front Mol Neurosci (2009)

Bottom Line: We compared gene expression patterns of neuroblasts obtained from two sites of the RMS, one closer to the site of origin, the subventricular zone, and one closer to the site of the final destination, the olfactory bulb (OB).Based on the validity of this approach, we chose four new networks and tested by functional in vivo analysis their involvement in neuroblast migration.Thus, knockdown of Calm1, Gria1 (GluA1) and Camk4 (calmodulin-signaling network), Hdac2 and Hsbp1 (Akt1-DNA transcription network), Vav3 and Ppm1a (growth factor signaling network) affected neuroblast migration to the OB.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Neurobiology, Interdisciplinary Center for Neurosciences Heidelberg, Germany.

ABSTRACT
Neuronal migration is a key process in the developing and adult brain. Numerous factors act on intracellular cascades of migrating neurons and regulate the final position of neurons. One robust migration route persists postnatally - the rostral migratory stream (RMS). To identify genes that govern neuronal migration in this unique structure, we isolated RMS neuroblasts by making use of transgenic mice that express EGFP in this cell population and performed microarray analysis on RNA. We compared gene expression patterns of neuroblasts obtained from two sites of the RMS, one closer to the site of origin, the subventricular zone, and one closer to the site of the final destination, the olfactory bulb (OB). We identified more than 400 upregulated genes, many of which were not known to be involved in migration. These genes were grouped into functional networks by bioinformatics analysis. Selecting a specific upregulated intracellular network, the cytoskeleton pathway, we confirmed by functional in vitro and in vivo analysis that the identified genes of this network affected RMS neuroblast migration. Based on the validity of this approach, we chose four new networks and tested by functional in vivo analysis their involvement in neuroblast migration. Thus, knockdown of Calm1, Gria1 (GluA1) and Camk4 (calmodulin-signaling network), Hdac2 and Hsbp1 (Akt1-DNA transcription network), Vav3 and Ppm1a (growth factor signaling network) affected neuroblast migration to the OB.

No MeSH data available.


Signaling networks upregulated in migrating neuroblasts. (A) Calmodulin-signaling network. (B) Akt1-DNA transcription network. Networks were identified by Ingenuity Pathway Analysis and subsequently modified using Bibliosphere, PathwayArchitect, GO and pathway databases. The intensity of the red color indicates the extent of gene upregulation. Connecting lines with arrowheads indicate activation of proteins, without arrowheads protein–protein interaction. Continuous and dashed lines are direct and indirect activation/interaction, respectively. Node description is indicated in the right upper corner.
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Figure 4: Signaling networks upregulated in migrating neuroblasts. (A) Calmodulin-signaling network. (B) Akt1-DNA transcription network. Networks were identified by Ingenuity Pathway Analysis and subsequently modified using Bibliosphere, PathwayArchitect, GO and pathway databases. The intensity of the red color indicates the extent of gene upregulation. Connecting lines with arrowheads indicate activation of proteins, without arrowheads protein–protein interaction. Continuous and dashed lines are direct and indirect activation/interaction, respectively. Node description is indicated in the right upper corner.

Mentions: The thorough functional analysis carried out for the members of the cytoskeleton pathway provides evidence that the upregulated genes identified by the microarray study are indeed important for migrating RMS neuroblasts, and that the analysis can be extended to other genes and pathways. There were numerous novel candidate networks comprising genes that were significantly upregulated in migrating neuroblasts (p-values ranging from 10−10 to 10−42), meriting further attention (Table 4 in Supplementary Material). Four networks were chosen for functional in vivo studies: calmodulin-signaling network, Akt1-DNA transcription network, GF signaling network and MAPK signaling network (Figures 4A,B and 5A,B, respectively, and Table 4 in Supplementary Material). These networks were chosen for further analysis firstly because associated p-values were high and secondly they comprised members that instigated our curiosity given that other studies had revealed their significance for neuronal processes not necessarily involved in migration. For instance calmodulin is known to be involved in calcium signaling and has been shown to play a role in numerous neuronal processes, including plasticity or neurotransmitter release (Xia and Storm, 2005). Furthermore, these networks comprise members that are also constituents of the above described and analyzed cytoskeleton pathway – e.g., Akt1 is a member of both the cytoskeleton and the Akt1-DNA transcription pathways. The occurrence of some genes in different pathways allows grouping them together in a large neuronal migratory signaling complex.


Major signaling pathways in migrating neuroblasts.

Khodosevich K, Seeburg PH, Monyer H - Front Mol Neurosci (2009)

Signaling networks upregulated in migrating neuroblasts. (A) Calmodulin-signaling network. (B) Akt1-DNA transcription network. Networks were identified by Ingenuity Pathway Analysis and subsequently modified using Bibliosphere, PathwayArchitect, GO and pathway databases. The intensity of the red color indicates the extent of gene upregulation. Connecting lines with arrowheads indicate activation of proteins, without arrowheads protein–protein interaction. Continuous and dashed lines are direct and indirect activation/interaction, respectively. Node description is indicated in the right upper corner.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2724029&req=5

Figure 4: Signaling networks upregulated in migrating neuroblasts. (A) Calmodulin-signaling network. (B) Akt1-DNA transcription network. Networks were identified by Ingenuity Pathway Analysis and subsequently modified using Bibliosphere, PathwayArchitect, GO and pathway databases. The intensity of the red color indicates the extent of gene upregulation. Connecting lines with arrowheads indicate activation of proteins, without arrowheads protein–protein interaction. Continuous and dashed lines are direct and indirect activation/interaction, respectively. Node description is indicated in the right upper corner.
Mentions: The thorough functional analysis carried out for the members of the cytoskeleton pathway provides evidence that the upregulated genes identified by the microarray study are indeed important for migrating RMS neuroblasts, and that the analysis can be extended to other genes and pathways. There were numerous novel candidate networks comprising genes that were significantly upregulated in migrating neuroblasts (p-values ranging from 10−10 to 10−42), meriting further attention (Table 4 in Supplementary Material). Four networks were chosen for functional in vivo studies: calmodulin-signaling network, Akt1-DNA transcription network, GF signaling network and MAPK signaling network (Figures 4A,B and 5A,B, respectively, and Table 4 in Supplementary Material). These networks were chosen for further analysis firstly because associated p-values were high and secondly they comprised members that instigated our curiosity given that other studies had revealed their significance for neuronal processes not necessarily involved in migration. For instance calmodulin is known to be involved in calcium signaling and has been shown to play a role in numerous neuronal processes, including plasticity or neurotransmitter release (Xia and Storm, 2005). Furthermore, these networks comprise members that are also constituents of the above described and analyzed cytoskeleton pathway – e.g., Akt1 is a member of both the cytoskeleton and the Akt1-DNA transcription pathways. The occurrence of some genes in different pathways allows grouping them together in a large neuronal migratory signaling complex.

Bottom Line: We compared gene expression patterns of neuroblasts obtained from two sites of the RMS, one closer to the site of origin, the subventricular zone, and one closer to the site of the final destination, the olfactory bulb (OB).Based on the validity of this approach, we chose four new networks and tested by functional in vivo analysis their involvement in neuroblast migration.Thus, knockdown of Calm1, Gria1 (GluA1) and Camk4 (calmodulin-signaling network), Hdac2 and Hsbp1 (Akt1-DNA transcription network), Vav3 and Ppm1a (growth factor signaling network) affected neuroblast migration to the OB.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Neurobiology, Interdisciplinary Center for Neurosciences Heidelberg, Germany.

ABSTRACT
Neuronal migration is a key process in the developing and adult brain. Numerous factors act on intracellular cascades of migrating neurons and regulate the final position of neurons. One robust migration route persists postnatally - the rostral migratory stream (RMS). To identify genes that govern neuronal migration in this unique structure, we isolated RMS neuroblasts by making use of transgenic mice that express EGFP in this cell population and performed microarray analysis on RNA. We compared gene expression patterns of neuroblasts obtained from two sites of the RMS, one closer to the site of origin, the subventricular zone, and one closer to the site of the final destination, the olfactory bulb (OB). We identified more than 400 upregulated genes, many of which were not known to be involved in migration. These genes were grouped into functional networks by bioinformatics analysis. Selecting a specific upregulated intracellular network, the cytoskeleton pathway, we confirmed by functional in vitro and in vivo analysis that the identified genes of this network affected RMS neuroblast migration. Based on the validity of this approach, we chose four new networks and tested by functional in vivo analysis their involvement in neuroblast migration. Thus, knockdown of Calm1, Gria1 (GluA1) and Camk4 (calmodulin-signaling network), Hdac2 and Hsbp1 (Akt1-DNA transcription network), Vav3 and Ppm1a (growth factor signaling network) affected neuroblast migration to the OB.

No MeSH data available.