Pierre Fabre

The hedgehog pathway promotes blood-brain barrier integrity and CNS immune quiescence

Hedgehog signaling is required for maintaining the integrity of the blood-brain barrier. The blood-brain barrier (BBB) is composed of tightly bound endothelial cells (ECs) and perivascular astrocytes that regulate central nervous system (CNS) homeostasis. We showed that astrocytes secrete Sonic hedgehog and that BBB ECs express Hedgehog (Hh) receptors, which together promote BBB formation and integrity during embryonic development and adulthood. Using pharmacological inhibition and genetic inactivation of the Hh signaling pathway in ECs, we also demonstrated a critical role of the Hh pathway in promoting the immune quiescence of BBB ECs by decreasing the expression of proinflammatory mediators and the adhesion and migration of leukocytes, in vivo and in vitro. Overall, the Hh pathway provides a barrier-promoting effect and an endogenous anti-inflammatory balance to CNS-directed immune attacks, as occurs in multiple sclerosis.

Boc is a receptor for sonic hedgehog in the guidance of commissural axons

In the spinal cord, sonic hedgehog (Shh) is secreted by the floor plate to control the generation of distinct classes of ventral neurons along the dorsoventral axis. Genetic and in vitro studies have shown that Shh also later acts as a midline-derived chemoattractant for commissural axons. However, the receptor(s) responsible for Shh attraction remain unknown. Here we show that two Robo-related proteins, Boc and Cdon, bind specifically to Shh and are therefore candidate receptors for the action of Shh as an axon guidance ligand. Boc is expressed by commissural neurons, and targeted disruption of Boc in mouse results in the misguidance of commissural axons towards the floor plate. RNA-interference-mediated knockdown of Boc impairs the ability of rat commissural axons to turn towards an ectopic source of Shh in vitro. Taken together, these data suggest that Boc is essential as a receptor for Shh in commissural axon guidance.

VEGF Mediates Commissural Axon Chemoattraction through Its Receptor Flk1

Growing axons are guided to their targets by attractive and repulsive cues. In the developing spinal cord, Netrin-1 and Shh guide commissural axons toward the midline. However, the combined inhibition of their activity in commissural axon turning assays does not completely abrogate turning toward floor plate tissue, suggesting that additional guidance cues are present. Here we show that the prototypic angiogenic factor VEGF is secreted by the floor plate and is a chemoattractant for commissural axons in vitro and in vivo. Inactivation of Vegf in the floor plate or of its receptor Flk1 in commissural neurons causes axon guidance defects, whereas Flk1 blockade inhibits turning of axons to VEGF in vitro. Similar to Shh and Netrin-1, VEGF-mediated commissural axon guidance requires the activity of Src family kinases. Our results identify VEGF and Flk1 as a novel ligand/receptor pair controlling commissural axon guidance.

Segregation of Ipsilateral Retinal Ganglion Cell Axons at the Optic Chiasm Requires the Shh Receptor Boc

The pattern of contralaterally and ipsilaterally projecting retinal ganglion cell (RGC) axons at the optic chiasm is essential for the establishment of binocular vision. Contralateral axons cross the chiasm midline as they progress from the optic nerve to the optic tract. In contrast, ipsilateral axons deviate from the chiasm and continue in the ipsilateral optic tract, avoiding the chiasm midline. The molecular mechanism underlying this phenomenon is not completely understood. Here we show that the Sonic Hedgehog (Shh) receptor Boc is enriched in ipsilateral RGCs of the developing retina. Together with the presence of Shh at the midline, this complementary expression pattern led us to hypothesize that Shh might repel ipsilateral RGC axons at the chiasm. Consistent with this hypothesis, we found that only Boc-positive RGC axons retract in vitro in response to Shh and that this response is lost in Boc mutant RGCs. In vivo, we show that Boc is required for the normal segregation of ipsilateral axons at the optic chiasm and, conversely, that Boc expression in contralateral RGCs prevents their axons from crossing the optic chiasm. Together, these results suggest that Shh repels ipsilateral RGC axons at the optic chiasm via its receptor Boc. This work identifies a novel molecular pathway required for the segregation of axons at the optic chiasm.

Science-policy interface: beyond Assessments

In their Policy Forum “The biodiversity and ecosystem services science-policy interface” (4 March, p. [1139][1]), C. Perrings et al. frame the new Intergovernmental Platform on Biodiversity and Ecosystem Services (IPBES) as a body responsible primarily for assessment. They consistently base their elaboration of the work of IPBES on the experiences of past assessments (such as the Millennium Assessment, the Global Biodiversity Outlook, and the Intergovernmental Panel on Climate Change) and interpret the Busan outcome [recommendations made by a 2010 intergovernmental conference ([ 1 ][2])] solely through the lens of how scientific knowledge is assessed. We believe that the blueprint suitability of previous assessments for the IPBES process is very limited. Strengthening the (mainly global-scale) scientific knowledge base behind assessments is important, but the goals of IPBES should be expanded.nnFirst, we should move beyond conventional scientific knowledge assessments that legitimize, almost exclusively, only peer-reviewed material. Knowledge established across all scales (especially the knowledge of local and indigenous peoples) and validated in multiple ways must be eligible for inclusion in IPBES processes. Changes in biodiversity are first experienced locally and thus many forms of local expertise have particular relevance for biodiversity issues ([ 2 ][3]). Second, we should link IPBES assessment results to decision-making at multiple spatial scales (including tackling biodiversity loss at the grassroots level).nnBoth of these goals require all aspects of capacity-building, including empowerment of different kinds of actors, to be reflected in the structural design of IPBES. To achieve this much broader set of objectives as laid out in the Busan outcome, including the explicit incorporation of local and indigenous knowledge, the IPBES structure should knit together existing multiscale networks ([ 3 ][4]) of scientific, policy, and stakeholder communities.nn1. [↵][5] United Nations Environment Programme, “Busan Outcome,” Busan, Korea, 7 to 11 June 2010 ([www.unep.org/pdf/SMT_Agenda_Item_5-Busan_Outcome.pdf][6]).n nn2. [↵][7] 1. W. Reidn et al. , Eds., Bridging Scales and Knowledge Systems: Concepts and Applications in Ecosystems (Island Press, Washington, DC, 2006).n nn3. [↵][8] Leipzig Workshop Recommendations for a Knowledge-Policy Interface for Biodiversity Governance, 4 October 2006 ([www.ufz.de/data/leipzig_recom_final4614.pdf][9]).nn [1]: http://www.sciencemag.org/content/331/6021/1139.fulln [2]: #ref-1n [3]: #ref-2n [4]: #ref-3n [5]: #xref-ref-1-1 View reference 1 in textn [6]: http://www.unep.org/pdf/SMT_Agenda_Item_5-Busan_Outcome.pdfn [7]: #xref-ref-2-1 View reference 2 in textn [8]: #xref-ref-3-1 View reference 3 in textn [9]: http://www.ufz.de/data/leipzig_recom_final4614.pdf

Pioneer midbrain longitudinal axons navigate using a balance of Netrin attraction and Slit repulsion

BackgroundLongitudinal axons grow parallel to the embryonic midline to connect distant regions of the central nervous system. Previous studies suggested that repulsive midline signals guide pioneer longitudinal axons by blocking their entry into the floor plate; however, the role of midline attractants, and whether attractant signals may cooperate with repulsive signals, remains unclear. In this study we investigated the navigation of a set of pioneer longitudinal axons, the medial longitudinal fasciculus, in mouse embryos mutant for the Netrin/Deleted in Colorectal Cancer (DCC) attractants, and for Slit repellents, as well as the responses of explanted longitudinal axons in vitro.ResultsIn mutants for Netrin1 chemoattractant or DCC receptor signaling, longitudinal axons shifted away from the ventral midline, suggesting that Netrin1/DCC signals act attractively to pull axons ventrally. Analysis of mutants in the three Slit genes, including Slit1/2/3 triple mutants, suggest that concurrent repulsive Slit/Robo signals push pioneer axons away from the ventral midline. Combinations of mutations between the Netrin and Slit guidance systems provided genetic evidence that the attractive and repulsive signals balance against each other. This balance is demonstrated in vitro using explant culture, finding that the cues can act directly on longitudinal axons. The explants also reveal an unexpected synergy of Netrin1 and Slit2 that promotes outgrowth.ConclusionsThese results support a mechanism in which longitudinal trajectories are positioned by a push-pull balance between opposing Netrin and Slit signals. Our evidence suggests that longitudinal axons respond directly and simultaneously to both attractants and repellents, and that the combined signals constrain axons to grow longitudinally.

Science-Policy Interface

In their Policy Forum “The biodiversity and ecosystem services science-policy interface” (4 March, p. [1139][1]), C. Perrings et al. frame the new Intergovernmental Platform on Biodiversity and Ecosystem Services (IPBES) as a body responsible primarily for assessment. They consistently base their elaboration of the work of IPBES on the experiences of past assessments (such as the Millennium Assessment, the Global Biodiversity Outlook, and the Intergovernmental Panel on Climate Change) and interpret the Busan outcome [recommendations made by a 2010 intergovernmental conference ([ 1 ][2])] solely through the lens of how scientific knowledge is assessed. We believe that the blueprint suitability of previous assessments for the IPBES process is very limited. Strengthening the (mainly global-scale) scientific knowledge base behind assessments is important, but the goals of IPBES should be expanded.nnFirst, we should move beyond conventional scientific knowledge assessments that legitimize, almost exclusively, only peer-reviewed material. Knowledge established across all scales (especially the knowledge of local and indigenous peoples) and validated in multiple ways must be eligible for inclusion in IPBES processes. Changes in biodiversity are first experienced locally and thus many forms of local expertise have particular relevance for biodiversity issues ([ 2 ][3]). Second, we should link IPBES assessment results to decision-making at multiple spatial scales (including tackling biodiversity loss at the grassroots level).nnBoth of these goals require all aspects of capacity-building, including empowerment of different kinds of actors, to be reflected in the structural design of IPBES. To achieve this much broader set of objectives as laid out in the Busan outcome, including the explicit incorporation of local and indigenous knowledge, the IPBES structure should knit together existing multiscale networks ([ 3 ][4]) of scientific, policy, and stakeholder communities.nn1. [↵][5] United Nations Environment Programme, “Busan Outcome,” Busan, Korea, 7 to 11 June 2010 ([www.unep.org/pdf/SMT_Agenda_Item_5-Busan_Outcome.pdf][6]).n nn2. [↵][7] 1. W. Reidn et al. , Eds., Bridging Scales and Knowledge Systems: Concepts and Applications in Ecosystems (Island Press, Washington, DC, 2006).n nn3. [↵][8] Leipzig Workshop Recommendations for a Knowledge-Policy Interface for Biodiversity Governance, 4 October 2006 ([www.ufz.de/data/leipzig_recom_final4614.pdf][9]).nn [1]: http://www.sciencemag.org/content/331/6021/1139.fulln [2]: #ref-1n [3]: #ref-2n [4]: #ref-3n [5]: #xref-ref-1-1 View reference 1 in textn [6]: http://www.unep.org/pdf/SMT_Agenda_Item_5-Busan_Outcome.pdfn [7]: #xref-ref-2-1 View reference 2 in textn [8]: #xref-ref-3-1 View reference 3 in textn [9]: http://www.ufz.de/data/leipzig_recom_final4614.pdf

Letter: Science-Policy Interface: Beyond Assessments

In their Policy Forum “The biodiversity and ecosystem services science-policy interface” (4 March, p. [1139][1]), C. Perrings et al. frame the new Intergovernmental Platform on Biodiversity and Ecosystem Services (IPBES) as a body responsible primarily for assessment. They consistently base their elaboration of the work of IPBES on the experiences of past assessments (such as the Millennium Assessment, the Global Biodiversity Outlook, and the Intergovernmental Panel on Climate Change) and interpret the Busan outcome [recommendations made by a 2010 intergovernmental conference ([ 1 ][2])] solely through the lens of how scientific knowledge is assessed. We believe that the blueprint suitability of previous assessments for the IPBES process is very limited. Strengthening the (mainly global-scale) scientific knowledge base behind assessments is important, but the goals of IPBES should be expanded.nnFirst, we should move beyond conventional scientific knowledge assessments that legitimize, almost exclusively, only peer-reviewed material. Knowledge established across all scales (especially the knowledge of local and indigenous peoples) and validated in multiple ways must be eligible for inclusion in IPBES processes. Changes in biodiversity are first experienced locally and thus many forms of local expertise have particular relevance for biodiversity issues ([ 2 ][3]). Second, we should link IPBES assessment results to decision-making at multiple spatial scales (including tackling biodiversity loss at the grassroots level).nnBoth of these goals require all aspects of capacity-building, including empowerment of different kinds of actors, to be reflected in the structural design of IPBES. To achieve this much broader set of objectives as laid out in the Busan outcome, including the explicit incorporation of local and indigenous knowledge, the IPBES structure should knit together existing multiscale networks ([ 3 ][4]) of scientific, policy, and stakeholder communities.nn1. [↵][5] United Nations Environment Programme, “Busan Outcome,” Busan, Korea, 7 to 11 June 2010 ([www.unep.org/pdf/SMT_Agenda_Item_5-Busan_Outcome.pdf][6]).n nn2. [↵][7] 1. W. Reidn et al. , Eds., Bridging Scales and Knowledge Systems: Concepts and Applications in Ecosystems (Island Press, Washington, DC, 2006).n nn3. [↵][8] Leipzig Workshop Recommendations for a Knowledge-Policy Interface for Biodiversity Governance, 4 October 2006 ([www.ufz.de/data/leipzig_recom_final4614.pdf][9]).nn [1]: http://www.sciencemag.org/content/331/6021/1139.fulln [2]: #ref-1n [3]: #ref-2n [4]: #ref-3n [5]: #xref-ref-1-1 View reference 1 in textn [6]: http://www.unep.org/pdf/SMT_Agenda_Item_5-Busan_Outcome.pdfn [7]: #xref-ref-2-1 View reference 2 in textn [8]: #xref-ref-3-1 View reference 3 in textn [9]: http://www.ufz.de/data/leipzig_recom_final4614.pdf

Letter to the editor: Science-Policy Interface: Beyond Assessments

In their Policy Forum “The biodiversity and ecosystem services science-policy interface” (4 March, p. [1139][1]), C. Perrings et al. frame the new Intergovernmental Platform on Biodiversity and Ecosystem Services (IPBES) as a body responsible primarily for assessment. They consistently base their elaboration of the work of IPBES on the experiences of past assessments (such as the Millennium Assessment, the Global Biodiversity Outlook, and the Intergovernmental Panel on Climate Change) and interpret the Busan outcome [recommendations made by a 2010 intergovernmental conference ([ 1 ][2])] solely through the lens of how scientific knowledge is assessed. We believe that the blueprint suitability of previous assessments for the IPBES process is very limited. Strengthening the (mainly global-scale) scientific knowledge base behind assessments is important, but the goals of IPBES should be expanded.nnFirst, we should move beyond conventional scientific knowledge assessments that legitimize, almost exclusively, only peer-reviewed material. Knowledge established across all scales (especially the knowledge of local and indigenous peoples) and validated in multiple ways must be eligible for inclusion in IPBES processes. Changes in biodiversity are first experienced locally and thus many forms of local expertise have particular relevance for biodiversity issues ([ 2 ][3]). Second, we should link IPBES assessment results to decision-making at multiple spatial scales (including tackling biodiversity loss at the grassroots level).nnBoth of these goals require all aspects of capacity-building, including empowerment of different kinds of actors, to be reflected in the structural design of IPBES. To achieve this much broader set of objectives as laid out in the Busan outcome, including the explicit incorporation of local and indigenous knowledge, the IPBES structure should knit together existing multiscale networks ([ 3 ][4]) of scientific, policy, and stakeholder communities.nn1. [↵][5] United Nations Environment Programme, “Busan Outcome,” Busan, Korea, 7 to 11 June 2010 ([www.unep.org/pdf/SMT_Agenda_Item_5-Busan_Outcome.pdf][6]).n nn2. [↵][7] 1. W. Reidn et al. , Eds., Bridging Scales and Knowledge Systems: Concepts and Applications in Ecosystems (Island Press, Washington, DC, 2006).n nn3. [↵][8] Leipzig Workshop Recommendations for a Knowledge-Policy Interface for Biodiversity Governance, 4 October 2006 ([www.ufz.de/data/leipzig_recom_final4614.pdf][9]).nn [1]: http://www.sciencemag.org/content/331/6021/1139.fulln [2]: #ref-1n [3]: #ref-2n [4]: #ref-3n [5]: #xref-ref-1-1 View reference 1 in textn [6]: http://www.unep.org/pdf/SMT_Agenda_Item_5-Busan_Outcome.pdfn [7]: #xref-ref-2-1 View reference 2 in textn [8]: #xref-ref-3-1 View reference 3 in textn [9]: http://www.ufz.de/data/leipzig_recom_final4614.pdf