ENS - Départment de biologie

Unmasking GluN1/GluN3A excitatory glycine NMDA receptors.

Frédérique Godfroid — 2018-12-21T16:05:13Z

Abstract

GluN3A and GluN3B are glycine-binding subunits belonging to the NMDA receptor (NMDAR) family that can assemble with the GluN1 subunit to form unconventional receptors activated by glycine alone. Functional characterization of GluN1/GluN3 NMDARs has been difficult. Here, we uncover two modalities that have transformative properties on GluN1/GluN3A receptors. First, we identify a compound, CGP-78608, which greatly enhances GluN1/GluN3A responses, converting small and rapidly desensitizing currents into large and stable responses. Second, we show that an endogenous GluN3A disulfide bond endows GluN1/GluN3A receptors with distinct redox modulation, profoundly affecting agonist sensitivity and gating kinetics. Under reducing conditions, ambient glycine is sufficient to generate tonic receptor activation. Finally, using CGP-78608 on P8-P12 mouse hippocampal slices, we demonstrate that excitatory glycine GluN1/GluN3A NMDARs are functionally expressed in native neurons, at least in the juvenile brain. Our work opens new perspectives on the exploration of excitatory glycine receptors in brain function and development.

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Nat Commun. 2018 Nov 13 ;9(1):4769. doi : 10.1038/s41467-018-07236-4.

Jean-François Brunet, lauréat du prix de la FRM : "Brixham Foundation 2018"

Frédérique Godfroid — 2018-12-06T14:59:44Z

Information

Natural Genetic Variation in a Multigenerational Phenotype in C. elegans

Frédérique Godfroid — 2018-12-06T14:09:47Z

Abstract

Although heredity mostly relies on the transmission of DNA sequence, additional molecular and cellular features are heritable across several generations. In the nematode Caenorhabditis elegans, insights into such unconventional inheritance result from two lines of work. First, the mortal germline (Mrt) phenotype was defined as a multigenerational phenotype whereby a selfing lineage becomes sterile after several generations, implying multigenerational memory [1, 2]. Second, certain RNAi effects are heritable over several generations in the absence of the initial trigger [3-5]. Both lines of work converged when the subset of Mrt mutants that are heat sensitive were found to closely correspond to mutants defective in the RNAi-inheritance machinery, including histone modifiers [6-9]. Here, we report the surprising finding that several C. elegans wild isolates display a heat-sensitive mortal germline phenotype in laboratory conditions : upon chronic exposure to higher temperatures, such as 25°C, lines reproducibly become sterile after several generations. This phenomenon is reversible, as it can be suppressed by temperature alternations at each generation, suggesting a non-genetic basis for the sterility. We tested whether natural variation in the temperature-induced Mrt phenotype was of genetic nature by building recombinant inbred lines between the isolates MY10 (Mrt) and JU1395 (non-Mrt). Using bulk segregant analysis, we detected two quantitative trait loci. After further recombinant mapping and genome editing, we identified the major causal locus as a polymorphism in the set-24 gene, encoding a SET- and SPK-domain protein. We conclude that C. elegans natural populations may harbor natural genetic variation in epigenetic inheritance phenomena.

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Curr Biol. 2018 Aug 20 ;28(16):2588-2596.e8. doi : 10.1016/j.cub.2018.05.091.

Cellular origin, tumour progression and pathogenic mechanisms of cutaneous neurofibromas revealed by mice with Nf1 knockout in boundary cap cells

Frédérique Godfroid — 2018-11-22T15:24:55Z

Abstract

Patients carrying an inactive NF1 allele develop tumours of Schwann cell origin called neurofibromas (NFs). Genetically engineered mouse models have significantly enriched our understanding of plexiform forms of NFs (pNFs). However, this has not been the case for cutaneous neurofibromas (cNFs), observed in all NF1 patients, as no previous model recapitulates their development. Here, we show that conditional Nf1 inactivation in Prss56-positive boundary cap cells leads to bona fide pNFs and cNFs. This work identifies subepidermal glia as a likely candidate for the cellular origin of cNFs, and provides insights on disease mechanisms, revealing a long, multistep pathological process in which inflammation-related signals play pivotal role. This new mouse model is an important asset for future clinical and therapeutic investigations of NF1-associated neurofibromas.

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Cancer Discov. 2018 Oct 22. pii : CD-18-0156. doi : 10.1158/2159-8290.CD-18-0156.

Active intermixing of indirect and direct neurons builds the striatal mosaic

Frédérique Godfroid — 2018-11-22T15:12:42Z

ABSTRACT

The striatum controls behaviors via the activity of direct and indirect pathway projection neurons (dSPN and iSPN) that are intermingled in all compartments. While such cellular mosaic ensures the balanced activity of the two pathways, its developmental origin and pattern remains largely unknown. Here, we show that both SPN populations are specified embryonically and intermix progressively through multidirectional iSPN migration. Using conditional mutant mice, we found that inactivation of the dSPN-specific transcription factor Ebf1 impairs selective dSPN properties, including axon pathfinding, while molecular and functional features of iSPN were preserved. Ebf1 mutation disrupted iSPN/dSPN intermixing, resulting in an uneven distribution. Such architectural defect was selective of the matrix compartment, highlighting that intermixing is a parallel process to compartment formation. Our study reveals while iSPN/dSPN specification is largely independent, their intermingling emerges from an active migration of iSPN, thereby providing a novel framework for the building of striatal architecture.

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Nat Commun. 2018 Nov 9 ;9(1):4725. doi : 10.1038/s41467-018-07171-4.

Whole-Brain Neuronal Activity Displays Crackling Noise Dynamics

Frédérique Godfroid — 2018-11-22T15:10:11Z

ABSTRACT

Previous studies suggest that the brain operates at a critical point in which phases of order and disorder coexist, producing emergent patterned dynamics at all scales and optimizing several brain functions. Here, we combined light-sheet microscopy with GCaMP zebrafish larvae to study whole-brain dynamics in vivo at near single-cell resolution. We show that spontaneous activity propagates in the brain's three-dimensional space, generating scale-invariant neuronal avalanches with time courses and recurrence times that exhibit statistical self-similarity at different magnitude, temporal, and frequency scales. This suggests that the nervous system operates close to a non-equilibrium phase transition, where a large repertoire of spatial, temporal, and interactive modes can be supported. Finally, we show that gap junctions contribute to the maintenance of criticality and that, during interactions with the environment (sensory inputs and self-generated behaviors), the system is transiently displaced to a more ordered regime, conceivably to limit the potential sensory representations and motor outcomes.

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Neuron. 2018 Nov 15. pii : S0896-6273(18)30953-X. doi : 10.1016/j.neuron.2018.10.045

An inter‐dimer allosteric switch controls NMDA receptor activity.

Frédérique Godfroid — 2018-11-06T15:07:25Z

Abstract

NMDA receptors (NMDARs) are glutamate‐gated ion channels that are key mediators of excitatory neurotransmission and synaptic plasticity throughout the central nervous system. They form massive heterotetrameric complexes endowed with unique allosteric capacity provided by eight extracellular clamshell‐like domains arranged as two superimposed layers. Despite an increasing number of full‐length NMDAR structures, how these domains cooperate in an intact receptor to control its activity remains poorly understood. Here, combining single‐molecule and macroscopic electrophysiological recordings, cysteine biochemistry, and in silico analysis, we identify a rolling motion at a yet unexplored interface between the two constitute dimers in the agonist‐binding domain (ABD) layer as a key structural determinant in NMDAR activation and allosteric modulation. This rotation acts as a gating switch that tunes channel opening depending on the conformation of the membrane‐distal N‐terminal domain (NTD) layer. Remarkably, receptors locked in a rolled state display “super‐activity” and resistance to NTD‐mediated allosteric modulators. Our work unveils how NMDAR domains move in a concerted manner to transduce long‐range conformational changes between layers and command receptor channel activity.

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EMBO Journal (2018) e99894, DOI 10.15252/embj.201899894

Microglia and early brain development : An intimate journey.

Frédérique Godfroid — 2018-10-25T08:02:22Z

Cross-talk between the nervous and immune systems has been well described in the context of adult physiology and disease. Recent advances in our understanding of immune cell ontogeny have revealed a notable interplay between neurons and microglia during the prenatal and postnatal emergence of functional circuits. This Review focuses on the brain, where the early symbiotic relationship between microglia and neuronal cells critically regulates wiring, contributes to sex-specific differences in neural circuits, and relays crucial information from the periphery, including signals derived from the microbiota. These observations underscore the importance of studying neurodevelopment as part of a broader framework that considers nervous system interactions with microglia in a whole-body context.

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Thion et al., Science 362, 185–189 (2018) 12 October 2018

Chromosome evolution at the origin of the ancestral vertebrate genome

Frédérique Godfroid — 2018-10-22T16:08:57Z

ABSTRACT

Background
It has been proposed that more than 450 million years ago, two successive whole genome duplications took place in a marine chordate lineage before leading to the common ancestor of vertebrates. A precise reconstruction of these founding events would provide a framework to better understand the impact of these early whole genome duplications on extant vertebrates.
Results
We reconstruct the evolution of chromosomes at the beginning of vertebrate evolution. We first compare 61 extant animal genomes to reconstruct the highly contiguous order of genes in a 326-million-year-old ancestral Amniota genome. In this genome, we establish a well-supported list of duplicated genes originating from the two whole genome duplications to identify tetrads of duplicated chromosomes. From this, we reconstruct a chronology in which a pre-vertebrate genome composed of 17 chromosomes duplicated to 34 chromosomes and was subject to seven chromosome fusions before duplicating again into 54 chromosomes. After the separation of the lineage of Gnathostomata (jawed vertebrates) from Cyclostomata (extant jawless fish), four more fusions took place to form the ancestral Euteleostomi (bony vertebrates) genome of 50 chromosomes.
Conclusions
These results firmly establish the occurrence of two whole genome duplications in the lineage that precedes the ancestor of vertebrates, resolving in particular the ambiguity raised by the analysis of the lamprey genome. This work provides a foundation for studying the evolution of vertebrate chromosomes from the standpoint of a common ancestor and particularly the pattern of duplicate gene retention and loss that resulted in the gene composition of extant vertebrate genomes.

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Genome Biol. 2018 Oct 17 ;19(1) : 166. doi : 10.1186/s13059-018-1559-1.

Clade diversification dynamics and the biotic and abiotic controls of speciation and extinction rates.

Frédérique Godfroid — 2018-10-11T08:49:07Z

Abstract

How ecological interactions, genetic processes, and environmental variability jointly shape the evolution of species diversity remains a challenging problem in biology. We developed an individual-based model of clade diversification to predict macroevolutionary dynamics when resource competition, genetic differentiation, and landscape fluctuations interact. Diversification begins with a phase of geographic adaptive radiation. Extinction rates rise sharply at the onset of the next phase. In this phase of niche self-structuring, speciation and extinction processes, albeit driven by biotic mechanisms (competition and hybridization), have essentially constant rates, determined primarily by the abiotic pace of landscape dynamics. The final phase of diversification begins when intense competition prevents dispersing individuals from establishing new populations. Species' ranges shrink, causing negative diversity-dependence of speciation rates. These results show how ecological and microevolutionary processes shape macroevolutionary dynamics and rates ; they caution against the notion of ecological limits to diversity, and suggest new directions for the phylogenetic analysis of diversification.

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Nat Commun. 2018 Aug 1 ;9(1):3013. doi : 10.1038/s41467-018-05419-7.