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The serotonin 6 receptor controls neuronal migration during corticogenesis via a ligand-independent Cdk5-dependent mechanism.

Jacobshagen M, Niquille M, Chaumont-Dubel S, Marin P, Dayer A - Development (2014)

Bottom Line: Cyclin-dependent kinase 5 (Cdk5) is a master regulator of pyramidal neuron migration.Recently, we have shown that Cdk5 binds to the serotonin 6 receptor (5-HT6R), a G protein-coupled receptor (GPCR).These data provide the first in vivo evidence of a role for constitutive activity at a GPCR in neocortical radial migration.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, University of Geneva Medical School, CH-1211 Geneva 4, Switzerland Department of Basic Neurosciences, University of Geneva Medical School, CH-1211 Geneva 4, Switzerland.

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In vivo downregulation of 5-HT6R induces persistent mispositioning of pyramidal neurons that maintain their superficial layer molecular identity. (A) In utero electroporation at E14.5 leads to a persistent mispositioning of 5-HT6R-shRNA1 TOM+ PNs at P7 in WM and deep cortical layers compared with scram-shRNA (**P<0.01, unpaired Student's t-test). (B,C) Immunohistochemistry (IHC) for CUX1 shows that mispositioned 5-HT6R-shRNA1 TOM+ PNs in deep cortical layers maintain a superficial layer molecular identity (B) and that the fraction of TOM+ PNs expressing CUX1 in cortical layers 2/3 is unchanged after 5-HT6R knockdown (C). (D,E) IHC showing that misplaced 5-HT6R-shRNA1 TOM+ PNs are not immunolabelled for CTIP2 (D) specifically expressed in layer 5 subcerebral projection neurons or for TLE4 (E) expressed in layer 6 thalamo-cortical projection neurons. PNs, pyramidal neurons; CUX1, Cut-like homeobox 1; CTIP2, COUP-TF-interacting protein 2; TLE4, transducin-like enhancer of split 4; WM, white matter. Data are mean±s.e.m. Scale bars: 100 µm in A and in low magnification views in B,D,E; 20 µm in C; 15 µm in high magnification views in B,D,E.
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DEV108043F2: In vivo downregulation of 5-HT6R induces persistent mispositioning of pyramidal neurons that maintain their superficial layer molecular identity. (A) In utero electroporation at E14.5 leads to a persistent mispositioning of 5-HT6R-shRNA1 TOM+ PNs at P7 in WM and deep cortical layers compared with scram-shRNA (**P<0.01, unpaired Student's t-test). (B,C) Immunohistochemistry (IHC) for CUX1 shows that mispositioned 5-HT6R-shRNA1 TOM+ PNs in deep cortical layers maintain a superficial layer molecular identity (B) and that the fraction of TOM+ PNs expressing CUX1 in cortical layers 2/3 is unchanged after 5-HT6R knockdown (C). (D,E) IHC showing that misplaced 5-HT6R-shRNA1 TOM+ PNs are not immunolabelled for CTIP2 (D) specifically expressed in layer 5 subcerebral projection neurons or for TLE4 (E) expressed in layer 6 thalamo-cortical projection neurons. PNs, pyramidal neurons; CUX1, Cut-like homeobox 1; CTIP2, COUP-TF-interacting protein 2; TLE4, transducin-like enhancer of split 4; WM, white matter. Data are mean±s.e.m. Scale bars: 100 µm in A and in low magnification views in B,D,E; 20 µm in C; 15 µm in high magnification views in B,D,E.

Mentions: In utero electroporation of 5-HT6R-shRNA1 induced a persistent mispositioning of PNs in the postnatal cortex. At P7, 5-HT6R-shRNA1 TOM+ PNs were significantly misplaced in deep cortical layers and in the underlying white matter (Fig. 2A). Displaced TOM+ cells found in deep cortical layers maintained their molecular identity of superficial layer PNs as a majority of them (72.1±4.9%) expressed the superficial layer-specific transcription factor CUX1 (Fig. 2B) (Greig et al., 2013). The percentage of TOM+ PNs expressing CUX1 in upper layers was not modified following 5-HT6R knockdown (Fig. 2C). Moreover, displaced TOM+ cells did not express the layer 5-specific transcription factor CTIP2 (Fig. 2D) or the layer 6-specific transcription factor TLE4 (Fig. 2E) (Greig et al., 2013).Fig. 2.


The serotonin 6 receptor controls neuronal migration during corticogenesis via a ligand-independent Cdk5-dependent mechanism.

Jacobshagen M, Niquille M, Chaumont-Dubel S, Marin P, Dayer A - Development (2014)

In vivo downregulation of 5-HT6R induces persistent mispositioning of pyramidal neurons that maintain their superficial layer molecular identity. (A) In utero electroporation at E14.5 leads to a persistent mispositioning of 5-HT6R-shRNA1 TOM+ PNs at P7 in WM and deep cortical layers compared with scram-shRNA (**P<0.01, unpaired Student's t-test). (B,C) Immunohistochemistry (IHC) for CUX1 shows that mispositioned 5-HT6R-shRNA1 TOM+ PNs in deep cortical layers maintain a superficial layer molecular identity (B) and that the fraction of TOM+ PNs expressing CUX1 in cortical layers 2/3 is unchanged after 5-HT6R knockdown (C). (D,E) IHC showing that misplaced 5-HT6R-shRNA1 TOM+ PNs are not immunolabelled for CTIP2 (D) specifically expressed in layer 5 subcerebral projection neurons or for TLE4 (E) expressed in layer 6 thalamo-cortical projection neurons. PNs, pyramidal neurons; CUX1, Cut-like homeobox 1; CTIP2, COUP-TF-interacting protein 2; TLE4, transducin-like enhancer of split 4; WM, white matter. Data are mean±s.e.m. Scale bars: 100 µm in A and in low magnification views in B,D,E; 20 µm in C; 15 µm in high magnification views in B,D,E.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
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DEV108043F2: In vivo downregulation of 5-HT6R induces persistent mispositioning of pyramidal neurons that maintain their superficial layer molecular identity. (A) In utero electroporation at E14.5 leads to a persistent mispositioning of 5-HT6R-shRNA1 TOM+ PNs at P7 in WM and deep cortical layers compared with scram-shRNA (**P<0.01, unpaired Student's t-test). (B,C) Immunohistochemistry (IHC) for CUX1 shows that mispositioned 5-HT6R-shRNA1 TOM+ PNs in deep cortical layers maintain a superficial layer molecular identity (B) and that the fraction of TOM+ PNs expressing CUX1 in cortical layers 2/3 is unchanged after 5-HT6R knockdown (C). (D,E) IHC showing that misplaced 5-HT6R-shRNA1 TOM+ PNs are not immunolabelled for CTIP2 (D) specifically expressed in layer 5 subcerebral projection neurons or for TLE4 (E) expressed in layer 6 thalamo-cortical projection neurons. PNs, pyramidal neurons; CUX1, Cut-like homeobox 1; CTIP2, COUP-TF-interacting protein 2; TLE4, transducin-like enhancer of split 4; WM, white matter. Data are mean±s.e.m. Scale bars: 100 µm in A and in low magnification views in B,D,E; 20 µm in C; 15 µm in high magnification views in B,D,E.
Mentions: In utero electroporation of 5-HT6R-shRNA1 induced a persistent mispositioning of PNs in the postnatal cortex. At P7, 5-HT6R-shRNA1 TOM+ PNs were significantly misplaced in deep cortical layers and in the underlying white matter (Fig. 2A). Displaced TOM+ cells found in deep cortical layers maintained their molecular identity of superficial layer PNs as a majority of them (72.1±4.9%) expressed the superficial layer-specific transcription factor CUX1 (Fig. 2B) (Greig et al., 2013). The percentage of TOM+ PNs expressing CUX1 in upper layers was not modified following 5-HT6R knockdown (Fig. 2C). Moreover, displaced TOM+ cells did not express the layer 5-specific transcription factor CTIP2 (Fig. 2D) or the layer 6-specific transcription factor TLE4 (Fig. 2E) (Greig et al., 2013).Fig. 2.

Bottom Line: Cyclin-dependent kinase 5 (Cdk5) is a master regulator of pyramidal neuron migration.Recently, we have shown that Cdk5 binds to the serotonin 6 receptor (5-HT6R), a G protein-coupled receptor (GPCR).These data provide the first in vivo evidence of a role for constitutive activity at a GPCR in neocortical radial migration.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, University of Geneva Medical School, CH-1211 Geneva 4, Switzerland Department of Basic Neurosciences, University of Geneva Medical School, CH-1211 Geneva 4, Switzerland.

Show MeSH