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Article: Cils et migrations neuronales.

Métin, Christine

2014 Volume 30, Issue 11, Page(s) 991–995

Abstract: In a landmark paper published in 1977, G. Albrecht-Buehler described a primary cilium on the surface of migrating fibroblasts, and noticed that cilia are oriented parallel to the direction of migration of fibroblasts. While the presence of a primary ... ...

Title translation	Cilia and neuronal migrations.
Abstract	In a landmark paper published in 1977, G. Albrecht-Buehler described a primary cilium on the surface of migrating fibroblasts, and noticed that cilia are oriented parallel to the direction of migration of fibroblasts. While the presence of a primary cilium on neural progenitors and on post-mitotic neurons was noted long ago, it has been observed on migrating cortical interneurons only recently. As in fibroblasts, the cilium of interneurons controls the directionality of migration. It plays an important role in the reorientation of cortical interneurons towards the cortical plate. The morphogen Shh, which is expressed in the migratory pathway of interneurons, is one of the signals that control this reorientation.
MeSH term(s)	Animals ; Cell Movement/physiology ; Cerebral Cortex/cytology ; Cerebral Cortex/embryology ; Cilia/physiology ; GABAergic Neurons/physiology ; GABAergic Neurons/ultrastructure ; Hedgehog Proteins/physiology ; Humans ; Interneurons/physiology ; Interneurons/ultrastructure ; Mice ; Nerve Tissue Proteins/physiology ; Patched Receptors ; Receptors, Cell Surface/physiology ; Receptors, G-Protein-Coupled/physiology ; Smoothened Receptor
Chemical Substances	Hedgehog Proteins ; Nerve Tissue Proteins ; Patched Receptors ; Receptors, Cell Surface ; Receptors, G-Protein-Coupled ; SMO protein, human ; Smo protein, mouse ; Smoothened Receptor
Language	French
Publishing date	2014-11
Publishing country	France
Document type	Journal Article ; Review
ZDB-ID	632733-3
ISSN	1958-5381 ; 0767-0974
ISSN (online)	1958-5381
ISSN	0767-0974
DOI	10.1051/medsci/20143011013
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Article ; Online: CXCL12 targets the primary cilium cAMP/cGMP ratio to regulate cell polarity during migration.

Atkins, Melody / Wurmser, Maud / Darmon, Michèle / Roche, Fiona / Nicol, Xavier / Métin, Christine

Nature communications

2023 Volume 14, Issue 1, Page(s) 8003

Abstract: Directed cell migration requires sustained cell polarisation. In migrating cortical interneurons, nuclear movements are directed towards the centrosome that organises the primary cilium signalling hub. Primary cilium-elicited signalling, and how it ... ...

Abstract	Directed cell migration requires sustained cell polarisation. In migrating cortical interneurons, nuclear movements are directed towards the centrosome that organises the primary cilium signalling hub. Primary cilium-elicited signalling, and how it affects migration, remain however ill characterised. Here, we show that altering cAMP/cGMP levels in the primary cilium by buffering cAMP, cGMP or by locally increasing cAMP, influences the polarity and directionality of migrating interneurons, whereas buffering cAMP or cGMP in the apposed centrosome compartment alters their motility. Remarkably, we identify CXCL12 as a trigger that targets the ciliary cAMP/cGMP ratio to promote sustained polarity and directed migration. We thereby uncover cAMP/cGMP levels in the primary cilium as a major target of extrinsic cues and as the steering wheel of neuronal migration.
MeSH term(s)	Cell Polarity ; Cilia/physiology ; Cyclic GMP ; Interneurons/physiology ; Cell Movement/physiology
Chemical Substances	Cyclic GMP (H2D2X058MU)
Language	English
Publishing date	2023-12-04
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-43645-w
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Article ; Online: PAK3 activation promotes the tangential to radial migration switch of cortical interneurons by increasing leading process dynamics and disrupting cell polarity.

Viou, Lucie / Atkins, Melody / Rousseau, Véronique / Launay, Pierre / Masson, Justine / Pace, Clarisse / Murakami, Fujio / Barnier, Jean-Vianney / Métin, Christine

Molecular psychiatry

2024

Abstract: Mutations of PAK3, a p21-activated kinase, are associated in humans with cognitive deficits suggestive of defective cortical circuits and with frequent brain structural abnormalities. Most human variants no longer exhibit kinase activity. Since GABAergic ...

Abstract	Mutations of PAK3, a p21-activated kinase, are associated in humans with cognitive deficits suggestive of defective cortical circuits and with frequent brain structural abnormalities. Most human variants no longer exhibit kinase activity. Since GABAergic interneurons express PAK3 as they migrate within the cortex, we here examined the role of PAK3 kinase activity in the regulation of cortical interneuron migration. During the embryonic development, cortical interneurons migrate a long distance tangentially and then re-orient radially to settle in the cortical plate, where they contribute to cortical circuits. We showed that interneurons expressing a constitutively kinase active PAK3 variant (PAK3-ca) extended shorter leading processes and exhibited unstable polarity. In the upper cortical layers, they entered the cortical plate and extended radially oriented processes. In the deep cortical layers, they exhibited erratic non-processive migration movements and accumulated in the deep pathway. Pharmacological inhibition of PAK3 kinase inhibited the radial migration switch of interneurons to the cortical plate and reduced their accumulation in the deep cortical layers. Interneurons expressing a kinase dead PAK3 variant (PAK3-kd) developed branched leading processes, maintained the same polarity during migration and exhibited processive and tangentially oriented movements in the cortex. These results reveal that PAK3 kinase activity, by promoting leading process shortening and cell polarity changes, inhibits the tangential processive migration of interneurons and favors their radial re- orientation and targeting to the cortical plate. They suggest that patients expressing PAK3 variants with impaired kinase activity likely present alterations in the cortical targeting of their GABAergic interneurons.
Language	English
Publishing date	2024-03-07
Publishing country	England
Document type	Journal Article
ZDB-ID	1330655-8
ISSN	1476-5578 ; 1359-4184
ISSN (online)	1476-5578
ISSN	1359-4184
DOI	10.1038/s41380-024-02483-y
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Article ; Online: Conserved rules in embryonic development of cortical interneurons.

Laclef, Christine / Métin, Christine

Seminars in cell & developmental biology

2017 Volume 76, Page(s) 86–100

Abstract: This review will focus on early aspects of cortical interneurons (cIN) development from specification to migration and final positioning in the human cerebral cortex. These mechanisms have been largely studied in the mouse model, which provides unique ... ...

Abstract	This review will focus on early aspects of cortical interneurons (cIN) development from specification to migration and final positioning in the human cerebral cortex. These mechanisms have been largely studied in the mouse model, which provides unique possibilities of genetic analysis, essential to dissect the molecular and cellular events involved in cortical development. An important goal here is to discuss the conservation and the potential divergence of these mechanisms, with a particular interest for the situation in the human embryo. We will thus cover recent works, but also revisit older studies in the light of recent data to better understand the developmental mechanisms underlying cIN differentiation in human. Because cIN are implicated in severe developmental disorders, understanding the molecular and cellular mechanisms controlling their differentiation might clarify some causes and potential therapeutic approaches to these important clinical conditions.
MeSH term(s)	Cell Differentiation ; Cerebral Cortex/embryology ; Humans ; Interneurons/physiology
Language	English
Publishing date	2017-09-14
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1312473-0
ISSN	1096-3634 ; 1084-9521
ISSN (online)	1096-3634
ISSN	1084-9521
DOI	10.1016/j.semcdb.2017.09.017
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Article ; Online: CXCL12 targets the primary cilium cAMP/cGMP ratio to regulate cell polarity during migration

Melody Atkins / Maud Wurmser / Michèle Darmon / Fiona Roche / Xavier Nicol / Christine Métin

Nature Communications, Vol 14, Iss 1, Pp 1-

2023 Volume 17

Abstract: Abstract Directed cell migration requires sustained cell polarisation. In migrating cortical interneurons, nuclear movements are directed towards the centrosome that organises the primary cilium signalling hub. Primary cilium-elicited signalling, and how ...

Abstract	Abstract Directed cell migration requires sustained cell polarisation. In migrating cortical interneurons, nuclear movements are directed towards the centrosome that organises the primary cilium signalling hub. Primary cilium-elicited signalling, and how it affects migration, remain however ill characterised. Here, we show that altering cAMP/cGMP levels in the primary cilium by buffering cAMP, cGMP or by locally increasing cAMP, influences the polarity and directionality of migrating interneurons, whereas buffering cAMP or cGMP in the apposed centrosome compartment alters their motility. Remarkably, we identify CXCL12 as a trigger that targets the ciliary cAMP/cGMP ratio to promote sustained polarity and directed migration. We thereby uncover cAMP/cGMP levels in the primary cilium as a major target of extrinsic cues and as the steering wheel of neuronal migration.
Keywords	Science ; Q
Language	English
Publishing date	2023-12-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: In Vitro Models to Analyze the Migration of MGE-Derived Interneurons.

Leclech, Claire / Métin, Christine

Methods in molecular biology (Clifton, N.J.)

2018 Volume 1749, Page(s) 145–161

Abstract: In the developing brain, MGE-derived interneuron precursors migrate tangentially long distances to reach the cortex in which they later establish connections with the principal cortical cells to control the activity of adult cortical circuits. ... ...

Abstract	In the developing brain, MGE-derived interneuron precursors migrate tangentially long distances to reach the cortex in which they later establish connections with the principal cortical cells to control the activity of adult cortical circuits. Interneuron precursors exhibit complex morphologies and migratory properties, which are difficult to study in the heterogeneous and uncontrolled in vivo environment. Here, we describe two in vitro models in which the migration environment of interneuron precursors is significantly simplified and where their migration can be observed for one to 3 days. In one model, MGE-derived interneuron precursors are cultured and migrate on a flat synthetic substrate. In the other model, fluorescent MGE-derived interneuron precursors migrate on a monolayer of dissociated cortical cells. In both models, cell movements can be recorded by time-lapse microscopy for dynamic analyses.
MeSH term(s)	Animals ; Cell Movement/physiology ; Cells, Cultured ; Humans ; Interneurons/cytology ; Mice ; Microscopy, Video/methods ; Signal Transduction/physiology ; Time-Lapse Imaging/methods
Language	English
Publishing date	2018-02-15
Publishing country	United States
Document type	Journal Article
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-4939-7701-7_12
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Article ; Online: Topographical cues control the morphology and dynamics of migrating cortical interneurons.

Leclech, Claire / Renner, Marianne / Villard, Catherine / Métin, Christine

Biomaterials

2019 Volume 214, Page(s) 119194

Abstract: In mammalian embryos, cortical interneurons travel long distances among complex three-dimensional tissues before integrating into cortical circuits. Several molecular guiding cues involved in this migration process have been identified, but the influence ...

Abstract	In mammalian embryos, cortical interneurons travel long distances among complex three-dimensional tissues before integrating into cortical circuits. Several molecular guiding cues involved in this migration process have been identified, but the influence of physical parameters remains poorly understood. In the present study, we have investigated in vitro the influence of the topography of the microenvironment on the migration of primary cortical interneurons released from mouse embryonic explants. We found that arrays of PDMS micro-pillars of 10 μm size and spacing, either round or square, influenced both the morphology and the migratory behavior of interneurons. Strikingly, most interneurons exhibited a single and long leading process oriented along the diagonals of the square pillared array, whereas leading processes of interneurons migrating in-between round pillars were shorter, often branched and oriented in all available directions. Accordingly, dynamic studies revealed that growth cone divisions were twice more frequent in round than in square pillars. Both soma and leading process tips presented forward directed movements within square pillars, contrasting with the erratic trajectories and more dynamic movements observed among round pillars. In support of these observations, long interneurons migrating in square pillars displayed tight bundles of stable microtubules aligned in the direction of migration. Overall, our results show that micron-sized topography provides global spatial constraints promoting the establishment of different morphological and migratory states. Remarkably, these different states belong to the natural range of migratory behaviors of cortical interneurons, highlighting the potential importance of topographical cues in the guidance of these embryonic neurons, and more generally in brain development.
MeSH term(s)	Animals ; Cell Movement/physiology ; Embryo, Mammalian/cytology ; Humans ; Interneurons/cytology ; Interneurons/metabolism ; Microscopy, Video ; Microtubules/metabolism ; Neurogenesis/physiology
Language	English
Publishing date	2019-05-14
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	603079-8
ISSN	1878-5905 ; 0142-9612
ISSN (online)	1878-5905
ISSN	0142-9612
DOI	10.1016/j.biomaterials.2019.05.005
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Article ; Online: Cilia: traffic directors along the road of cortical development.

Métin, Christine / Pedraza, Maria

The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry

2014 Volume 20, Issue 5, Page(s) 468–482

Abstract: While the presence of a primary cilium on neural progenitors and on post-mitotic neurons was noted long ago, a primary cilium has been observed on migrating cortical interneurons only recently. As in fibroblasts, the cilium of interneurons controls the ... ...

Abstract	While the presence of a primary cilium on neural progenitors and on post-mitotic neurons was noted long ago, a primary cilium has been observed on migrating cortical interneurons only recently. As in fibroblasts, the cilium of interneurons controls the directionality of migration. It plays an important role in the reorientation of cortical interneurons toward the cortical plate. The morphogen Shh, which is expressed in the migratory pathway of interneurons, is one of the signals that control this reorientation. After a short description of the migratory pathways of cortical interneurons, we focus on cellular mechanisms that allow interneurons to reorient their trajectory during their long-distance migration. Then we examine the role of the primary cilium in cell migration and how ciliogenesis might be related to the migration cycle in interneurons. Finally, we review the molecular mechanisms at the basis of the sensory function of the primary cilium and examine how Shh signals could influence the migratory behavior of cortical interneurons. These novel data provide a cellular basis to further understanding cognitive deficits associated with human ciliopathies.
MeSH term(s)	Animals ; Cell Movement/physiology ; Cerebral Cortex/growth & development ; Cerebral Cortex/physiology ; Cilia/physiology ; Hedgehog Proteins/metabolism ; Humans ; Interneurons/physiology
Chemical Substances	Hedgehog Proteins
Language	English
Publishing date	2014-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1233753-5
ISSN	1089-4098 ; 1073-8584
ISSN (online)	1089-4098
ISSN	1073-8584
DOI	10.1177/1073858414543151
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Article: Topographical cues control the morphology and dynamics of migrating cortical interneurons

Leclech, Claire / Renner, Marianne / Villard, Catherine / Métin, Christine

Biomaterials. 2019 Sept., v. 214

2019

Abstract	In mammalian embryos, cortical interneurons travel long distances among complex three-dimensional tissues before integrating into cortical circuits. Several molecular guiding cues involved in this migration process have been identified, but the influence of physical parameters remains poorly understood. In the present study, we have investigated in vitro the influence of the topography of the microenvironment on the migration of primary cortical interneurons released from mouse embryonic explants.We found that arrays of PDMS micro-pillars of 10 μm size and spacing, either round or square, influenced both the morphology and the migratory behavior of interneurons. Strikingly, most interneurons exhibited a single and long leading process oriented along the diagonals of the square pillared array, whereas leading processes of interneurons migrating in-between round pillars were shorter, often branched and oriented in all available directions. Accordingly, dynamic studies revealed that growth cone divisions were twice more frequent in round than in square pillars. Both soma and leading process tips presented forward directed movements within square pillars, contrasting with the erratic trajectories and more dynamic movements observed among round pillars. In support of these observations, long interneurons migrating in square pillars displayed tight bundles of stable microtubules aligned in the direction of migration.Overall, our results show that micron-sized topography provides global spatial constraints promoting the establishment of different morphological and migratory states. Remarkably, these different states belong to the natural range of migratory behaviors of cortical interneurons, highlighting the potential importance of topographical cues in the guidance of these embryonic neurons, and more generally in brain development.
Keywords	brain ; interneurons ; mice ; microtubules ; migratory behavior ; topography
Language	English
Dates of publication	2019-09
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	603079-8
ISSN	0142-9612
ISSN	0142-9612
DOI	10.1016/j.biomaterials.2019.05.005
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Four years of early benefit assessment of new drugs in Germany: a qualitative study on methodological requirements for quality of life data.

Blome, Christine / Augustin, Matthias / Metin, Hidayet / Lohrberg, David

The European journal of health economics : HEPAC : health economics in prevention and care

2017 Volume 18, Issue 2, Page(s) 181–193

Abstract: Background: Since 2011, an early benefit assessment (EBA) of new drugs constricts free price setting in Germany. According to the Pharmaceutical Market Restructuring Act (AMNOG), pharmaceutical companies are obliged to demonstrate added benefit of new ... ...

Abstract	Background: Since 2011, an early benefit assessment (EBA) of new drugs constricts free price setting in Germany. According to the Pharmaceutical Market Restructuring Act (AMNOG), pharmaceutical companies are obliged to demonstrate added benefit of new drugs over comparative treatment. Benefit is usually evaluated by the Institute for Quality and Efficiency in Health Care (IQWiG). The final appraisal is made by the Federal Joint Committee, Germany's highest-ranking decision body in the health sector, triggering drug prize negotiations between companies and statutory health insurance funds. One of four evaluation criteria is quality of life (QoL). QoL outcomes have, however, only rarely been pivotal in EBAs. Objective: This study determined methodological requirements for QoL measurement and data presentation in the EBA. Design: In a qualitative content analysis, documents of all EBAs completed by 2014 were searched for the term QoL. Relevant passages of all EBAs of 2011-2013 were independently extracted and reduced to key content by two researchers. Recurring patterns were identified and verified through comparison with EBAs of 2014. Results: We identified a range of requirements regarding QoL assessment, analysis, presentation, and interpretation, which go beyond official regulations. Disease-specific questionnaires are preferred and have to be validated according to certain standards and in the respective patient group. Effects must exceed the minimal important difference, which in turn must be validated in compliance with specific requirements. Often, instruments were not accepted as QoL measures, sometimes inconsistently across EBAs. Another frequent reason for non-acceptance of QoL data was that more than 30 % of randomized patients could not be analyzed due to missing data. Conclusions: Non-compliance with methodological requirements for QoL evidence impairs chances for positive benefit evaluation.
MeSH term(s)	Bias ; Cost-Benefit Analysis/methods ; Costs and Cost Analysis ; Drug Approval/legislation & jurisprudence ; Drug Approval/methods ; Drug Industry/methods ; Germany ; Humans ; Qualitative Research ; Quality of Life ; Reproducibility of Results ; Research Design ; Surveys and Questionnaires/standards
Language	English
Publishing date	2017-03
Publishing country	Germany
Document type	Journal Article
ZDB-ID	2045253-6
ISSN	1618-7601 ; 1618-7598
ISSN (online)	1618-7601
ISSN	1618-7598
DOI	10.1007/s10198-016-0765-6
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