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The embryonic MGE, LGE and cortex contribute progenitors to the adult SVZ
Poster abstracts / Int. J. Devl Neuroscience 24 (2006) 495–603
indicate Shh and Hip adenoviral vectors should be valuable to further analyze Shh effects in the SVZ and in other brain areas. Keywords: Morphogen; Adult neural stem cells; Bromodeoxyuridine; Subventricular zone doi:10.1016/j.ijdevneu.2006.09.068
Intrahippocampal transplantation of transgenic IL-1ra over-expressing glial cells blocks IL-1-mediated stressinduced decline in memory and neurogenesis O.B. Menachem 1,2,∗ , I. Goshen 1,2 , Y.B. Menahem 1,2 , T. Kreisel 1,2 , E. Reinhartz 1,2 , T.B. Hur 1,2 , R. Yirmiya 1,2 Hebrew University of Jerusalem, Israel; Hebrew University Hospital, Israel
2 Hadassah-
Previous studies demonstrated that elevation in the levels of the pro-inflammatory cytokine interleukin-1 (IL-1) within the brain is involved in mediating the memory impairments associated with inflammation and aging. In the present study, we used a model of chronic stress, in which each mouse was isolated in an individual cage for 3 weeks. In both the contextual fear conditioning (FC) test and the spatial version of the Morris water maze (MWM) paradigm, which depend on hippocampal functioning, isolated mice displayed significant memory impairments. Isolation had no effect on the hippocampus independent auditory-cued FC and the non-spatial version of the MWM. Isolation caused a significant elevation in hippocampal IL-1 levels as well as a significant decrease in hippocampal neurogenesis. To explore the role of hippocampal IL-1 in stress-induced memory impairments and suppressed neurogenesis, neural precursor cells (NPCs) were isolated from neonatal mice with transgenic over-expression of IL-1 receptor antagonist (IL-1raTG) under the GFAP promoter, labeled with PKH-26 and transplanted into the hippocampus of WT mice. Three weeks later, transplanted cells, expressing mainly astrocytic markers, could be observed within the hippocampus, and the levels of hippocampal IL-1ra were markedly elevated. In isolated mice, transplantation of IL1raTG NPCs completely rescued the memory impairments and significantly increased hippocampal neurogenesis, compared with isolated mice transplanted with WT cells or sham-operated only. The transplantation had no effect in non-stressed mice. These findings elucidate the role of IL-1 in the pathophysiology of chronic stress and suggest that the intra-hippocampal transplantation of transgenic IL-1raTG NPCs may provide a useful therapeutic procedure for IL-1-mediated memory disturbances in other conditions, particularly neurodegenerative diseases. Keywords: Interleukin-1; Neural precursor cells; Stress; Neurogenesis doi:10.1016/j.ijdevneu.2006.09.069
[P6] The embryonic MGE, LGE and cortex contribute progenitors to the adult SVZ K.M. Young ∗ , N. Kessaris, M. Fogarty, R. Haines, W.D. Richardson The Wolfson Institute for Biomedical Research, UK
[P5]
1 The
497
The embryonic neuroepithelium can be subdivided into at least three domains: the cortical neuroepithelium, the medial ganglionic eminence (MGE) and the lateral ganglionic eminence (LGE). Each region has a specific gene expression pattern and neurogenic potential during embryogenesis. However, the contribution of each embryonic germinal zone to the neural stem cells of the adult subventricular zone (SVZ) has not been clearly defined. To address this question we used four transgenic lines that express Cre recombinase in defined neuroepithelial domains: Gsh2-Cre (to label the LGE and MGE), Nkx2.1-Cre (MGE), Emx1-Cre (cortex) and Dbx1-Cre (cortico-striatal sulcus) (Kessaris et al., 2006; Fogarty et al., 2005). When one of these lines was crossed with a Rosa26-GFP Cre-dependent reporter, GFP was activated in the corresponding neuroepithelial domain and retained in all of its cell progeny, allowing their nature and location to be traced into adulthood. Visualization of GFP in the adult SVZ identified a significant contribution of cells from all parts of the embryonic neuroepithelium, including the cortex. The cortically derived SVZ cells did not result from de novo recombination in the adult, because SVZ cells were labeled in adult Emx1-CreERT2 /Rosa26-GFP transgenics, even when Cre was activated transiently with tamoxifen at E9.5. Furthermore, all regions of the embryonic telencephalon contributed progenitor/stem cells to the adult SVZ, reflected by the generation of GFP-positive SVZ-derived neurospheres from each Cre line/Rosa26-GFP. We are currently investigating the differentiation potential of neurospheres with different embryonic ancestry. Most GFP-positive neurospheres derived from the LGE, cortico-striatal sulcus and cortex readily generated betaIII-tubulin-positive neurons in vitro. However, neurospheres derived from the MGE generated primarily glia, suggesting that the embryonic region of origin might be a source of SVZ precursor heterogeneity. Keywords: Subventricular zone; Stem cell; Cre recombinase; Differentiation References Fogarty, M., Richardson, W.D., Kessaris, N., 2005. Development 132, 1951–1959. Kessaris, N., Fogarty, M., et al., 2006. Nat. Neurosci. 9, 173–179.
doi:10.1016/j.ijdevneu.2006.09.070
indicate Shh and Hip adenoviral vectors should be valuable to further analyze Shh effects in the SVZ and in other brain areas. Keywords: Morphogen; Adult neural stem cells; Bromodeoxyuridine; Subventricular zone doi:10.1016/j.ijdevneu.2006.09.068
Intrahippocampal transplantation of transgenic IL-1ra over-expressing glial cells blocks IL-1-mediated stressinduced decline in memory and neurogenesis O.B. Menachem 1,2,∗ , I. Goshen 1,2 , Y.B. Menahem 1,2 , T. Kreisel 1,2 , E. Reinhartz 1,2 , T.B. Hur 1,2 , R. Yirmiya 1,2 Hebrew University of Jerusalem, Israel; Hebrew University Hospital, Israel
2 Hadassah-
Previous studies demonstrated that elevation in the levels of the pro-inflammatory cytokine interleukin-1 (IL-1) within the brain is involved in mediating the memory impairments associated with inflammation and aging. In the present study, we used a model of chronic stress, in which each mouse was isolated in an individual cage for 3 weeks. In both the contextual fear conditioning (FC) test and the spatial version of the Morris water maze (MWM) paradigm, which depend on hippocampal functioning, isolated mice displayed significant memory impairments. Isolation had no effect on the hippocampus independent auditory-cued FC and the non-spatial version of the MWM. Isolation caused a significant elevation in hippocampal IL-1 levels as well as a significant decrease in hippocampal neurogenesis. To explore the role of hippocampal IL-1 in stress-induced memory impairments and suppressed neurogenesis, neural precursor cells (NPCs) were isolated from neonatal mice with transgenic over-expression of IL-1 receptor antagonist (IL-1raTG) under the GFAP promoter, labeled with PKH-26 and transplanted into the hippocampus of WT mice. Three weeks later, transplanted cells, expressing mainly astrocytic markers, could be observed within the hippocampus, and the levels of hippocampal IL-1ra were markedly elevated. In isolated mice, transplantation of IL1raTG NPCs completely rescued the memory impairments and significantly increased hippocampal neurogenesis, compared with isolated mice transplanted with WT cells or sham-operated only. The transplantation had no effect in non-stressed mice. These findings elucidate the role of IL-1 in the pathophysiology of chronic stress and suggest that the intra-hippocampal transplantation of transgenic IL-1raTG NPCs may provide a useful therapeutic procedure for IL-1-mediated memory disturbances in other conditions, particularly neurodegenerative diseases. Keywords: Interleukin-1; Neural precursor cells; Stress; Neurogenesis doi:10.1016/j.ijdevneu.2006.09.069
[P6] The embryonic MGE, LGE and cortex contribute progenitors to the adult SVZ K.M. Young ∗ , N. Kessaris, M. Fogarty, R. Haines, W.D. Richardson The Wolfson Institute for Biomedical Research, UK
[P5]
1 The
497
The embryonic neuroepithelium can be subdivided into at least three domains: the cortical neuroepithelium, the medial ganglionic eminence (MGE) and the lateral ganglionic eminence (LGE). Each region has a specific gene expression pattern and neurogenic potential during embryogenesis. However, the contribution of each embryonic germinal zone to the neural stem cells of the adult subventricular zone (SVZ) has not been clearly defined. To address this question we used four transgenic lines that express Cre recombinase in defined neuroepithelial domains: Gsh2-Cre (to label the LGE and MGE), Nkx2.1-Cre (MGE), Emx1-Cre (cortex) and Dbx1-Cre (cortico-striatal sulcus) (Kessaris et al., 2006; Fogarty et al., 2005). When one of these lines was crossed with a Rosa26-GFP Cre-dependent reporter, GFP was activated in the corresponding neuroepithelial domain and retained in all of its cell progeny, allowing their nature and location to be traced into adulthood. Visualization of GFP in the adult SVZ identified a significant contribution of cells from all parts of the embryonic neuroepithelium, including the cortex. The cortically derived SVZ cells did not result from de novo recombination in the adult, because SVZ cells were labeled in adult Emx1-CreERT2 /Rosa26-GFP transgenics, even when Cre was activated transiently with tamoxifen at E9.5. Furthermore, all regions of the embryonic telencephalon contributed progenitor/stem cells to the adult SVZ, reflected by the generation of GFP-positive SVZ-derived neurospheres from each Cre line/Rosa26-GFP. We are currently investigating the differentiation potential of neurospheres with different embryonic ancestry. Most GFP-positive neurospheres derived from the LGE, cortico-striatal sulcus and cortex readily generated betaIII-tubulin-positive neurons in vitro. However, neurospheres derived from the MGE generated primarily glia, suggesting that the embryonic region of origin might be a source of SVZ precursor heterogeneity. Keywords: Subventricular zone; Stem cell; Cre recombinase; Differentiation References Fogarty, M., Richardson, W.D., Kessaris, N., 2005. Development 132, 1951–1959. Kessaris, N., Fogarty, M., et al., 2006. Nat. Neurosci. 9, 173–179.
doi:10.1016/j.ijdevneu.2006.09.070