Dystroglycan Adds More Sugars to the Midline Cocktail

In this issue of Neuron, Wright et al. (2012) identify two novel mediators of α-dystroglycan glycosylation in mouse and unravel a novel function of glycosylated dystroglycan in axon guidance by providing evidence for direct binding of α-DG to the midline chemorepellent Slit2

Local circuit amplification of spatial selectivity in the hippocampus

Local circuit architecture facilitates the emergence of feature selectivity in the cerebral cortex1. In the hippocampus, it remains unknown whether local computations supported by specific connectivity motifs2 regulate the spatial receptive fields of pyramidal cells3. Here we developed an in vivo electroporation method for monosynaptic retrograde tracing4 and optogenetics manipulation at single-cell resolution to interrogate the dynamic interaction of place cells with their microcircuitry during navigation. We found a local circuit mechanism in CA1 whereby the spatial tuning of an individual place cell can propagate to a functionally recurrent subnetwork5 to which it belongs. The emergence of place fields in individual neurons led to the development of inverse selectivity in a subset of their presynaptic interneurons, and recruited functionally coupled place cells at that location. Thus, the spatial selectivity of single CA1 neurons is amplified through local circuit plasticity to enable effective multi-neuronal representations that can flexibly scale environmental features locally without degrading the feedforward input structure

Evolution et mécanismes moléculaires de la formation des commissures

Chez les espèces ayant une symétrie morphologique bilatérale, les connections entre la gauche et la droite au sein du système nerveux sont appelées commissures. Le développement de nouveaux circuits commissuraux et la modification des circuits existants ont accompagné l’émergence de caractéristiques neurobiologiques essentielles. D’un point de vue moléculaire, le guidage des commissures dépend de couplage ligand-récepteur tels que Netrin-1/DCC, responsable de l’attraction des axones commissuraux, et tel que Slit/Robo3, responsable de la répulsion des axones ayant traversé la ligne médiane. Plusieurs commissures ne se développent pas en absence d’un unique récepteur, le Robo3, contestant ainsi une présumée redondance moléculaire. Tout d’abord, il est impérial de caractériser le mécanisme moléculaire sous-jacent à cette fonction unique de Robo3 chez les mammifères et au cours de l’évolution. Ensuite, nous visons à extrapoler vers une indentification de nouvelles molécules impliquées dans le développement commissural. Nos travaux ouvrent la voie à une réévaluation du contrôle développemental assuré par Robo3 au sein du système commissural des mammifères. Par biochimie fonctionnelle, nous avons observé que Robo3 du mammifère ni se lie, ni ne réagit aux slits. Par ailleurs, Robo3 interagit avec DCC, ce qui produit une phosphorylation intracellulaire sélective de Robo3 par l’entremise de la Nétrine-1. Cette dernière n’a pas d’effet attractif sur les neurones pontiques dépourvus de Robo3; phénomène qui peut être rétabli chez des souris Robo3 -/- par l’expression de Robo3 mammifère, mais non par l’expression de Robo3 non-mammifère. En conclusion, nous démontrons que la fonction de Robo3 a été spécifiquement convertie lors de l’évolution des mammifères. Une telle diversification mécanistique dérivée de l’évolution moléculaire d’un gène spécifique est susceptible d’être à la base de la précision du contrôle des mouvements volontaires chez les mammifères.In species with bilateral morphological symmetry, connections between left and right in the nervous system are called commissures. The development of novel commissural circuits and modification of existing ones have accompanied the emergence of key neurobiological features in vertebrate evolution. Molecularly, guidance of commissures relies on ligand-receptor pairs such as Netrin-1/DCC mediating attraction of commissural axons to, and Slit/Robo mediated repulsion of post-crossing axons away from the midline. Arguing against assumed molecular redundancy, many commissures fail to develop in absence of a single receptor, Robo3. The objective of the current work is threefold: first, it sets out to characterize the molecular mechanisms underlying this unique function of Robo3 in mammals and evolutionarily across species. Secondly, we aim to extrapolate towards the identification of new molecules important for commissure development to lastly functionally evaluate some of these putative novel commissural signaling pathways. Our work paves the way to a complete reevaluation of Robo3-mediated developmental control in mammalian commissural systems. Using functional biochemistry, we find that mammalian Robo3 does neither bind nor respond to Slits. Moreover, Robo3 interacts with DCC and Netrin-1 selectively triggers intracellular phosphorylation of mammalian Robo3. Netrin-1 fails to attract pontine neurons lacking Robo3 and attraction can be restored in Robo3-/- mice by expression of mammalian, but not nonmammalian, Robo3. Conclusively, we show that Robo3 function has been uniquely converted during mammalian evolution. Such mechanistic diversification through molecular evolution in one specific gene likely underlies fine-tuning of mammalian voluntary movement control

Slit-Robo signaling

International audienceSlits are secreted proteins that bind to Roundabout (Robo) receptors. Slit-Robo signaling is best known for mediating axon repulsion in the developing nervous system. However, in recent years the functional repertoire of Slits and Robo has expanded tremendously and Slit-Robo signaling has been linked to roles in neurogenesis, angiogenesis and cancer progression among other processes. Likewise, our mechanistic understanding of Slit-Robo signaling has progressed enormously. Here, we summarize new insights into Slit-Robo evolutionary and system-dependent diversity, receptor-ligand interactions, signaling crosstalk and receptor activation

Local circuit amplification of spatial selectivity in the hippocampus

Local circuit architecture facilitates the emergence of feature selectivity in the cerebral cortex1. In the hippocampus, it remains unknown whether local computations supported by specific connectivity motifs2 regulate the spatial receptive fields of pyramidal cells3. Here we developed an in vivo electroporation method for monosynaptic retrograde tracing4 and optogenetics manipulation at single-cell resolution to interrogate the dynamic interaction of place cells with their microcircuitry during navigation. We found a local circuit mechanism in CA1 whereby the spatial tuning of an individual place cell can propagate to a functionally recurrent subnetwork5 to which it belongs. The emergence of place fields in individual neurons led to the development of inverse selectivity in a subset of their presynaptic interneurons, and recruited functionally coupled place cells at that location. Thus, the spatial selectivity of single CA1 neurons is amplified through local circuit plasticity to enable effective multi-neuronal representations that can flexibly scale environmental features locally without degrading the feedforward input structure

Commissural neurons transgress the cns/pns boundary in absence of ventricular zone-derived netrin 1

During the development of the central nervous system (CNS), only motor axons project into peripheral nerves. Little is known about the cellular and molecular mechanisms that control the development of a boundary at the CNS surface and prevent CNS neuron emigration from the neural tube. It has previously been shown that a subset of spinal cord commissural axons abnormally invades sensory nerves in Ntn1 hypomorphic embryos and Dcc knockouts. However, whether netrin 1 also plays a similar role in the brain is unknown. In the hindbrain, precerebellar neurons migrate tangentially under the pial surface, and their ventral migration is guided by netrin 1. Here, we show that pontine neurons and inferior olivary neurons, two types of precerebellar neurons, are not confined to the CNS in Ntn1 and Dcc mutant mice, but that they invade the trigeminal, auditory and vagus nerves. Using a Ntn1 conditional knockout, we show that netrin 1, which is released at the pial surface by ventricular zone progenitors is responsible for the CNS confinement of precerebellar neurons. We propose, that netrin 1 distribution sculpts the CNS boundary by keeping CNS neurons in netrin 1-rich domains.This work was supported by grants from the Agence Nationale de la Recherche (ANR-14-CE13-0004-01) (to A.C.). It was performed in the frame of the Labex Lifesenses (ANR-10-LABX-65) supported by French state funds managed by the Agence Nationale de la Recherche within the Investissements d'Avenir programme under ANR-11-IDEX-0004-02 (to A.C.).Peer reviewe

Signaling Switch of the Axon Guidance Receptor Robo3 during Vertebrate Evolution

International audienceDevelopment of neuronal circuits is controlled by evolutionarily conserved axon guidance molecules, including Slits, the repulsive ligands for roundabout (Robo) receptors, and Netrin-1, which mediates attraction through the DCC receptor. We discovered that the Robo3 receptor fundamentally changed its mechanism of action during mammalian evolution. Unlike other Robo receptors, mammalian Robo3 is not a high-affinity receptor for Slits because of specific substitutions in the first immunoglobulin domain. Instead, Netrin-1 selectively triggers phosphorylation of mammalian Robo3 via Src kinases. Robo3 does not bind Netrin-1 directly but interacts with DCC. Netrin-1 fails to attract pontine neurons lacking Robo3, and attraction can be restored in Robo3(-/-) mice by expression of mammalian, but not nonmammalian, Robo3. We propose that Robo3 evolution was key to sculpting the mammalian brain by converting a receptor for Slit repulsion into one that both silences Slit repulsion and potentiates Netrin attraction