Published : 2020/05/19 in Neuron
Whole-Neuron Synaptic Mapping Reveals Spatially Precise Excitatory/Inhibitory Balance Limiting Dendritic and Somatic Spiking
Daniel Maxim Iascone, Yujie Li, Uygar Sumbul, ..., Idan Segev, Hanchuan Peng, Franck Polleux

The balance between excitatory and inhibitory (E and I) synapses is thought to be critical for information processing in neural circuits. However, little is known about the spatial principles of E and I synaptic organization across the entire dendritic tree of mammalian neurons. We developed a new open-source reconstruction platform for mapping the size and spatial distribution of E and I synapses received by individual genetically-labeled layer 2/3 (L2/3) cortical pyramidal neurons (PNs) in vivo. We mapped over 90,000 E and I synapses across twelve L2/3 PNs and uncovered structured organization of E and I synapses across dendritic domains as well as within individual dendritic segments. Despite significant domain-specific variation in the absolute density of E and I synapses, their ratio is strikingly balanced locally across dendritic segments. Computational modeling indicates that this spatially precise E/I balance dampens dendritic voltage fluctuations and strongly impacts neuronal firing output.
Published : 2019/12/26 in Journal of Bone and Mineral Research
Rac1 Inhibition Via Srgap2 Restrains Inflammatory Osteoclastogenesis and Limits the Clastokine, SLIT3
Bongjin Shin, Justine Kupferman, Ewoud Schmidt, Franck Polleux, Anne M Delany, and Sun-Kyeong Lee

The Rac1-specific guanosine triphosphatase (GTPase)-activating protein Slit-Robo GAP2 (Srgap2) is dramatically upregulated during RANKL-induced osteoclastogenesis. Srgap2 interacts with the cell membrane to locally inhibit activity of Rac1. In this study, we determined the role of Srgap2 in the myeloid lineage on bone homeostasis and the osteoclastic response to TNFα treatment. The bone phenotype of mice specifically lacking Srgap2 in the myeloid lineage (Srgap2 f/f :LysM-Cre; Srgap2 conditional knockout [cKO]) was investigated using histomorphometric analysis, in vitro cultures and Western blot analysis. Similar methods were used to determine the impact of TNFα challenge on osteoclast formation in Srgap2 cKO mice. Bone parameters in male Srgap2 cKO mice were unaffected. However, female cKO mice displayed higher trabecular bone volume due to increased osteoblast surface and bone formation rate, whereas osteoclastic parameters were unaltered. In vitro, cells from Srgap2 cKO had strongly enhanced Rac1 activation, but RANKL-induced osteoclast formation was unaffected. In contrast, conditioned medium from Srgap2 cKO osteoclasts promoted osteoblast differentiation and had increased levels of the bone anabolic clastokine SLIT3, providing a possible mechanism for increased bone formation in vivo. Rac1 is rapidly activated by the inflammatory cytokine TNFα. Supracalvarial injection of TNFα caused an augmented osteoclastic response in Srgap2 cKO mice. In vitro, cells from Srgap2 cKO mice displayed increased osteoclast formation in response to TNFα. We conclude that Srgap2 plays a prominent role in limiting osteoclastogenesis during inflammation through Rac1, and restricts expression of the paracrine clastokine SLIT3, a positive regulator of bone formation. © 2019 American Society for Bone and Mineral Research.
Published : 2019/12/08 in Scientific Reports
The human-specific paralogs SRGAP2B and SRGAP2C differentially modulate SRGAP2A- dependent synaptic development
Ewoud R. E. Schmidt, Justine V. Kupferman, Michelle Stackmann & Franck Polleux

Human-specific gene duplications (HSGDs) have recently emerged as key modifiers of brain development and evolution. However, the molecular mechanisms underlying the function of HSGDs remain often poorly understood. In humans, a truncated duplication of SRGAP2A led to the emergence of two human-specific paralogs: SRGAP2B and SRGAP2C. The ancestral copy SRGAP2A limits synaptic density and promotes maturation of both excitatory (E) and inhibitory (I) synapses received by cortical pyramidal neurons (PNs). SRGAP2C binds to and inhibits all known functions of SRGAP2A leading to an increase in E and I synapse density and protracted synapse maturation, traits characterizing human cortical neurons. Here, we demonstrate how the evolutionary changes that led to the emergence of SRGAP2 HSGDs generated proteins that, in neurons, are intrinsically unstable and, upon hetero- dimerization with SRGAP2A, reduce SRGAP2A levels in a proteasome-dependent manner. Moreover, we show that, despite only a few non-synonymous mutations specifically targeting arginine residues, SRGAP2C is unique compared to SRGAP2B in its ability to induce long-lasting changes in synaptic density throughout adulthood. These mutations led to the ability of SRGAP2C to inhibit SRGAP2A function and thereby contribute to the emergence of human-specific features of synaptic development during evolution.
Published : 2019/03/27 in Developmental cell
Leukocyte Cytoskeleton Polarization Is Initiated by Plasma Membrane Curvature from Cell Attachment
Chunguang Ren, Qianying Yuan, Martha Braun, ..., Erdem Karatekin, Wenwen Tang, Dianqing Wu

The molecular mechanisms controlling cell polarization are incompletely understood. Ren and Yuan et al. show that local increase in plasma membrane (PM) curvature resulting from cell attachment recruits and polarizes an inverse FBAR domain protein SRGAP2 to initiate cell cytoskeleton polarization, which is important for neutrophil adhesion to endothelium.
Published : 2018/10/14 in Nature Communications
Haploinsufficiency of autism spectrum disorder candidate gene NUAK1 impairs cortical development and behavior in mice
Virginie Courchet, Amanda J. Roberts, Géraldine Meyer-Dilhet, Peggy Del Carmine, Tommy L. Lewis Jr, Franck Polleux & Julien Courchet

Recently, numerous rare de novo mutations have been identified in patients diagnosed with autism spectrum disorders (ASD). However, despite the predicted loss-of-function nature of some of these de novo mutations, the affected individuals are heterozygous carriers, which would suggest that most of these candidate genes are haploinsufficient and/or lead to expression of dominant-negative forms of the protein. Here, we tested this hypothesis with the candidate ASD gene Nuak1 that we previously identified for its role in the development of cortical connectivity. We report that Nuak1 is haploinsufficient in mice with regard to its function in cortical development. Furthermore Nuak1+/− mice show a combination of abnormal behavioral traits ranging from defective spatial memory consolidation, defects in social novelty (but not social preference) and abnormal sensorimotor gating. Overall, our results demonstrate that Nuak1 haploinsufficiency leads to defects in the development of cortical connectivity and a complex array of behavorial deficits.
Published : 2018/09/26 in Scientific Reports
Correlated Light-Serial Scanning Electron Microscopy (CoLSSEM) for ultrastructural visualization of single neurons in vivo
Yusuke Hirabayashi, Juan Carlos Tapia, Franck Polleux

A challenging aspect of neuroscience revolves around mapping the synaptic connections within neural circuits (connectomics) over scales spanning several orders of magnitude (nanometers to meters). Despite significant improvements in serial section electron microscopy (SSEM) technologies, several major roadblocks have impaired its general applicability to mammalian neural circuits. In the present study, we introduce a new approach that circumvents some of these roadblocks by adapting a genetically-encoded ascorbate peroxidase (APEX2) as a fusion protein to a membrane-targeted fluorescent reporter (CAAX-Venus), and introduce it in single pyramidal neurons in vivo using extremely sparse in utero cortical electroporation. This approach allows us to perform Correlated Light-SSEM (CoLSSEM), a variant of Correlated Light-EM (CLEM), on individual neurons, reconstructing their dendritic and axonal arborization in a targeted way via combination of high-resolution confocal microscopy, and subsequent imaging of its ultrastructural features and synaptic connections with ATUM-SEM (automated tape-collecting ultramicrotome - scanning electron microscopy) technology. Our method significantly will improve the feasibility of large-scale reconstructions of neurons within a circuit, and permits the description of some ultrastructural features of identified neurons with their functional and/or structural connectivity, one of the main goal of connectomics.
Published : 2018/03/26 in Current opinion in physiology
Emerging roles of mitochondria in synaptic transmission and neurodegeneration
Annie Lee, Yusuke Hirabayashi, Seok-Kyu Kwon, Tommy L. Lewis, Jr, and Franck Polleux

Mitochondria play numerous critical physiological functions in neurons including ATP production, Ca2+ regulation, lipid synthesis, ROS signaling, and the ability to trigger apoptosis. Recently developed technologies, including in vivo 2-photon imaging in awake behaving mice revealed that unlike in the peripheral nervous system (PNS), mitochondrial transport decreases strikingly along the axons of adult neurons of the central nervous system (CNS). Furthermore, the improvements of genetically-encoded biosensors have enabled precise monitoring of the spatial and temporal impact of mitochondria on Ca2+, ATP and ROS homeostasis in a compartment-specific manner. Here, we discuss recent findings that begin to unravel novel physiological and pathophysiological properties of neuronal mitochondria at synapses. We also suggest new directions in the exploration of mitochondrial function in synaptic transmission, plasticity and neurodegeneration.
Published : 2017/10/30 in Science
ER-mitochondria tethering by PDZD8 regulates Ca2+ dynamics in mammalian neurons
Yusuke Hirabayashi,* Seok-Kyu Kwon,* Hunki Paek, Wolfgang M. Pernice, Maëla A. Paul, Jinoh Lee, Parsa Erfani, Ashleigh Raczkowski, Donald S. Petrey, Liza A. Pon, Franck Polleux

Interfaces between organelles are emerging as critical platforms for many biological responses in eukaryotic cells. In yeast, the ERMES complex is an endoplasmic reticulum (ER)–mitochondria tether composed of four proteins, three of which contain a SMP (synaptotagmin-like mitochondrial-lipid binding protein) domain. No functional ortholog for any ERMES protein has been identified in metazoans. Here, we identified PDZD8 as an ER protein present at ER-mitochondria contacts. The SMP domain of PDZD8 is functionally orthologous to the SMP domain found in yeast Mmm1. PDZD8 was necessary for the formation of ER-mitochondria contacts in mammalian cells. In neurons, PDZD8 was required for calcium ion (Ca2+) uptake by mitochondria after synaptically induced Ca2+-release from ER and thereby regulated cytoplasmic Ca2+ dynamics. Thus, PDZD8 represents a critical ER-mitochondria tethering protein in metazoans. We suggest that ER-mitochondria coupling is involved in the regulation of dendritic Ca2+ dynamics in mammalian neurons.
Published : 2017/04/27 in Science
Multicluster Pcdh diversity is required for mouse olfactory neural circuit assembly
George Mountoufaris, Weisheng V. Chen, Yusuke Hirabayashi, Sean O’Keeffe, Maxime Chevee, Chiamaka L. Nwakeze, Franck Polleux, Tom Maniatis

The vertebrate clustered protocadherin (Pcdh) cell surface proteins are encoded by three closely linked gene clusters (Pcdha, Pcdhb, and Pcdhg). Here, we show that all three gene clusters functionally cooperate to provide individual mouse olfactory sensory neurons (OSNs) with the cell surface diversity required for their assembly into distinct glomeruli in the olfactory bulb. Although deletion of individual Pcdh clusters had subtle phenotypic consequences, the loss of all three clusters (tricluster deletion) led to a severe axonal arborization defect and loss of self-avoidance. By contrast, when endogenous Pcdh diversity is overridden by the expression of a single–tricluster gene repertoire (a and b and g), OSN axons fail to converge to form glomeruli, likely owing to contact-mediated repulsion between axons expressing identical combinations of Pcdh isoforms.
Published : 2016/07/19 in Neuron
SRGAP2 and its human-specific paralog co-regulate the development of excitatory and inhibitory synapses
Matteo Fossati, Rocco Pizzarelli, Ewoud R. Schmidt, Justine V. Kupferman, David Stroebel, Franck Polleux, Cécile Charrier

The proper function of neural circuits requires spatially and temporally balanced development of excitatory and inhibitory synapses. However, the molecular mechanisms coordinating excitatory and inhibitory synaptogenesis remain unknown. Here we demonstrate that SRGAP2A and its human-specific paralog SRGAP2C co-regulate the development of excitatory and inhibitory synapses in cortical pyramidal neurons in vivo. SRGAP2A promotes synaptic maturation, and ultimately the synaptic accumulation of AMPA and GABAA receptors, by interacting with key components of both excitatory and inhibitory postsynaptic scaffolds, Homer and Gephyrin. Furthermore, SRGAP2A limits the density of both types of synapses via its Rac1-GAP activity. SRGAP2C inhibits all identified functions of SRGAP2A, protracting the maturation and increasing the density of excitatory and inhibitory synapses. Our results uncover a molecular mechanism coordinating critical features of synaptic development and suggest that human-specific duplication of SRGAP2 might have contributed to the emergence of unique traits of human neurons while preserving the excitation/inhibition balance.
Published : 2015/05/05 in Cell Reports
SNAREs controlling vesicular release of BDNF and development of callosal axons
Masafumi Shimojo, Julien Courchet, Simon Pieraut, Nina Torabi-Rander, Richard Sando, III, Franck Polleux, Anton Maximov

- BDNF is a secreted protein that regulates neuronal development and plasticity - Vesicular exocytosis of BDNF is driven by SNAREs, Syb2, SNAP25, and SNAP47 - Unlike Syb2 and SNAP25, SNAP47 appears to be unnecessary for neurotransmission - Loss of BDNF or SNAP47 in callosal neurons diminishes branching of their axons
Published : 2014/04/04 in Current opinion in neurobiology
Involvement of ‘stress–response’ kinase pathways in Alzheimer’s disease progression
Georges Mairet-Coello, Franck Polleux

Alzheimer’s disease (AD) is the most prevalent cause of dementia, affecting more than 25 million people worldwide. Current models of the pathophysiological mechanisms of AD suggest that the accumulation of soluble oligomeric forms of amyloid-b (Ab) peptides causes early loss of excitatory synapses and impairs synaptic plasticity. The signaling pathways mediating Ab oligomer-induced impairment of synaptic plasticity and loss of excitatory synapses are only beginning to be unraveled. Here, we review recent evidence supporting the critical contribution of conserved ‘stress– response’ kinase pathways in AD progression.
Published : 2013/09/15 in The Journal of Cell Biology
Cellular and molecular mechanisms underlying axon formation, growth, and branching
Tommy L. Lewis Jr., Julien Courchet, and Franck Polleux

Proper brain wiring during development is pivotal for adult brain function. Neurons display a high degree of polar- ization both morphologically and functionally, and this polarization requires the segregation of mRNA, proteins, and lipids into the axonal or somatodendritic domains. Re- cent discoveries have provided insight into many aspects of the cell biology of axonal development including axon specification during neuronal polarization, axon growth, and terminal axon branching during synaptogenesis.
Published : 2013/06/19 in Cell
Terminal Axon Branching Is Regulated by the LKB1-NUAK1 Kinase Pathway via Presynaptic Mitochondrial Capture
Julien Courchet, Tommy Lewis, Jr., Sohyon Lee, Virginie Courchet, Deng-Yuan Liou, Shinichi Aizawa, Franck Polleux

The molecular mechanisms underlying the axon arborization of mammalian neurons are poorly understood but are critical for the establishment of functional neural circuits. We identified a pathway defined by two kinases, LKB1 and NUAK1, required for cortical axon branching in vivo. Conditional dele- tion of LKB1 after axon specification or knockdown of NUAK1 drastically reduced axon branching in vivo, whereas their overexpression was sufficient to increase axon branching. The LKB1-NUAK1 pathway controls mitochondria immobilization in axons. Using manipulation of Syntaphilin, a protein neces- sary and sufficient to arrest mitochondrial transport specifically in the axon, we demonstrate that the LKB1-NUAK1 kinase pathway regulates axon branching by promoting mitochondria immobiliza- tion. Finally, we show that LKB1 and NUAK1 are necessary and sufficient to immobilize mitochondria specifically at nascent presynaptic sites. Our results unravel a link between presynaptic mitochondrial capture and axon branching.
Published : 2013/04/09 in Neuron
The CAMKK2-AMPK Kinase Pathway Mediates the Synaptotoxic Effects of Ab Oligomers through Tau Phosphorylation
Georges Mairet-Coello, Julien Courchet, Simon Pieraut, Virginie Courchet, Anton Maximov, Franck Polleux

Amyloid-b 1–42 (Ab42) oligomers are synaptotoxic for excitatory cortical and hippocampal neurons and might play a role in early stages of Alzheimer’s disease (AD) progression. Recent results suggested that Ab42 oligomers trigger activation of AMP- activated kinase (AMPK), and its activation is increased in the brain of patients with AD. We show that increased intracellular calcium [Ca2+]i induced by NMDA receptor activation or membrane depolar- ization activates AMPK in a CAMKK2-dependent manner. CAMKK2 or AMPK overactivation is suffi- cient to induce dendritic spine loss. Conversely, inhibiting their activity protects hippocampal neu- rons against synaptotoxic effects of Ab42 oligomers in vitro and against the loss of dendritic spines observed in the human APPSWE,IND-expressing transgenic mouse model in vivo. AMPK phosphory- lates Tau on KxGS motif S262, and expression of Tau S262A inhibits the synaptotoxic effects of Ab42 oligomers. Our results identify a CAMKK2-AMPK- Tau pathway as a critical mediator of the synapto- toxic effects of Ab42 oligomers.
Published : 2012/04/30 in Cell
Inhibition of SRGAP2 Function by Its Human-Specific Paralogs Induces Neoteny during Spine Maturation
Cécile Charrier, Kaumudi Joshi, Jaeda Coutinho-Budd, Ji-Eun Kim, Nelle Lambert, Jacqueline de Marchena, Wei-Lin Jin, Pierre Vanderhaeghen, Anirvan Ghosh, Takayuki Sassa, Franck Polleux

Structural genomic variations represent a major driving force of evolution, and a burst of large segmental gene duplications occurred in the human lineage during its separation from nonhuman primates. SRGAP2, a gene recently implicated in neocortical development, has undergone two human-specific duplications. Here, we find that both duplications (SRGAP2B and SRGAP2C) are partial and encode a truncated F-BAR domain. SRGAP2C is expressed in the developing and adult human brain and dimerizes with ancestral SRGAP2 to inhibit its function. In the mouse neocortex, SRGAP2 promotes spine maturation and limits spine density. Expression of SRGAP2C phenocopies SRGAP2 deficiency. It underlies sustained radial migration and leads to the emergence of human-specific features, including neoteny during spine maturation and increased density of longer spines. These results suggest that inhibition of SRGAP2 function by its human-specific paralogs has contributed to the evolution of the human neocortex and plays an im- portant role during human brain development.
Published : 2011/03/20 in PNAS
AMP-activated protein kinase (AMPK) activity is not required for neuronal development but regulates axogenesis during metabolic stress
Tyisha Williams, Julien Courchet, Benoit Viollet, Jay E. Brenman and Franck Polleux

Mammalian brain connectivity requires the coordinated production and migration of billions of neurons and the formation of axons and dendrites. The LKB1/Par4 kinase is required for axon formation during cortical development in vivo partially through its ability to activate SAD-A/B kinases. LKB1 is a master kinase phosphorylating and activating at least 11 other serine/threonine kinases including the metabolic sensor AMP-activated protein kinase (AMPK), which defines this branch of the kinome. A recent study using a gene-trap allele of the β1 regulatory subunit of AMPK suggested that AMPK catalytic activity is required for proper brain development includ- ing neurogenesis and neuronal survival. We used a genetic loss- of-function approach producing AMPKα1/α2-null cortical neurons to demonstrate that AMPK catalytic activity is not required for cortical neurogenesis, neuronal migration, polarization, or survival. However, we found that application of metformin or AICAR, potent AMPK acti- vators, inhibit axogenesis and axon growth in an AMPK-dependent manner. We show that inhibition of axon growth mediated by AMPK overactivation requires TSC1/2-mediated inhibition of the mamma- lian target of rapamycin (mTOR) signaling pathway. Our results dem- onstrate that AMPK catalytic activity is not required for early neural development in vivo but its overactivation during metabolic stress impairs neuronal polarization in a mTOR-dependent manner.
Published : 2010/03/31 in Cold Spring Harbor Perspectives in Biology
Initiating and Growing an Axon
F. Polleux and William Snider

The ability of neurons to form a single axon and multiple dendrites underlies the directional flow of information transfer in the central nervous system. Dendrites and axons are molecu- larly and functionally distinct domains. Dendrites integrate synaptic inputs, triggering the generation of action potentials at the level of the soma. Action potentials then propagate along the axon, which makes presynaptic contacts onto target cells. This article reviews what is known about the cellular and molecular mechanisms underlying the ability of neurons to initiate and extend a single axon during development. Remarkably, neurons can polarize to form a single axon, multiple dendrites, and later establish functional synaptic contacts in reductionist in vitro conditions. This approach became, and remains, the domi- nant model to study axon initiation and growth and has yielded the identification of many molecules that regulate axon formation in vitro (Dotti et al. 1988). At present, only a few of the genes identified using in vitro approaches have been shown to be required for axon initiation and outgrowth in vivo. In vitro, axon initiation and elongation are largely intrinsic properties of neurons that are established in the absence of relevant extracellular cues. However, the importance of extracellular cues to axon initiation and outgrowth in vivo is emerging as a major theme in neural development (Barnes and Polleux 2009). In this article, we focus our attention on the extracellular cues and signaling pathways required in vivo for axon initiation and axon extension.
Published : 2009/04/12 in Neuron
KCC2 Expression Promotes the Termination of Cortical Interneuron Migration in a Voltage-Sensitive Calcium-Dependent Manner
Dante Bortone and Franck Polleux

The molecular mechanisms controlling the termina- tion of cortical interneuron migration are unknown. Here, we demonstrate that, prior to synaptogenesis, migrating interneurons change their responsiveness to ambient GABA from a motogenic to a stop signal. We found that, during migration into the cortex, ambient GABA and glutamate initially stimulate the motility of interneurons through both GABAA and AMPA/NMDA receptor activation. Once in the cortex, upregulation of the potassium-chloride cotransporter KCC2 is both necessary and sufficient to reduce inter- neuron motility through its ability to reduce membrane potential upon GABAA receptor activation, which decreases the frequency of spontaneous intracellular calcium transients initiated by L-type voltage-sensi- tive calcium channel (VSCC) activation. Our results suggest a mechanism whereby migrating interneu- rons determine the relative density of surrounding interneurons and principal cells through their ability to sense the combined extracellular levels of ambient glutamate and GABA once GABAA receptor activation becomes hyperpolarizing.
Published : 2008/05/11 in PLoS Biology
Topography of Thalamic Projections Requires Attractive and Repulsive Functions of Netrin-1 in the Ventral Telencephalon
Ashton W Powell, Takayuki Sassa, Yongqin Wu, Marc Tessier-Lavigne, Franck Polleux

The functional properties of each structure in the central nervous system are critically dependent on the precision of neuronal connectivity. The cerebral cortex in particular is a highly organized structure divided into many distinct cortical areas underlying important sensory, motor, and cognitive functions in the brain. Each primary cortical area receives its synaptic inputs from the periphery via the dorsal thalamus. The main relay station for sensory information to the cortex, the thalamus, can be divided into specific nuclei projecting topographically to individual cortical areas. How is the complex topography of thalamic axon projection to individual cortical areas specified during development? Recent evidence demonstrated that thalamic axons are routed to different cortical domains before they enter the cortex, by putative axon guidance cues present in the ventral forebrain. In the present study, we provide evidence that a secreted axon guidance cue, Netrin-1, expressed in a long-range gradient in the ventral forebrain, plays a critical role in the establishment of the topography of thalamic projections by directing different subsets of axons to specific cortical domains. These results provide important insights into the molecular mechanisms responsible for shaping the topographical patterns of thalamocortical axon projections in mammals.
Published : 2007/09/17 in Neuron Previews
The Ups and Downs of Neural Progenitors: Cep120 and TACCs Control Interkinetic Nuclear Migration
S. Guerrier and F. Polleux

The nuclei of dividing neural progenitors undergo a cell-cycle-dependent change in position along the apico-basal axis known as interkinetic nuclear migration (INM). The functional relationship between INM and the mode of division of neural progenitors remains elusive, in part because its regulation at the molecular level is poorly understood. In this issue of Neuron, Xie et al. identify two centrosomal proteins (Cep120 and TACCs) regulating the INM of cortical neural progenitors.
Published : 2005/05/04 in Neuron MiniReview
Genetic Mechanisms Specifying Cortical Connectivity: Let’s Make Some Projections Together
Franck Polleux

Great neuroanatomists of the twentieth century rec- ognized that the cerebral cortex of mammals is the single most complex structure of the central nervous system both in terms of neuronal diversity and con- nectivity. Understanding the cellular and molecular mechanisms specifying the afferent and efferent con- nectivity in the neocortex may seem like a daunting task. However, recent technical advances have greatly improved our ability to (1) profile gene expression of neuronal populations isolated based on their connec- tional properties, (2) manipulate gene expression in specific neuronal populations, and (3) visualize their ax- onal projections in vivo. These new tools are revolution- izing our ability to identify the molecular mechanisms patterning afferent and efferent cortical projections.
Published : 2004/07/26 in Trends Neuroscience
Developmental mechanisms patterning thalamocortical projections: intrinsic, extrinsic and in between
Pierre Vanderhaeghen, Franck Polleux

Roger Sperry proposed 40 years ago that topographic neural connections are established through complementary expression of chemoaffinity labels in projecting neurons and their final targets. This led to the identification of ephrins as key molecular cues controlling the topography of retinotectal projections. Recent studies have revealed a surprising twist to this model, shedding light on the developmental mechanisms patterning the projections between the thalamus and the cortex: ephrins, unexpectedly expressed in an intermediate target, control the establishment of topography of axonal projections between these two structures. The same cues are re-used later to control the mapping of thalamocortical projections within a given cortical area, which strikingly illustrates how a limited set of genes can contribute to generate several levels of complexity of a neuronal network.

Zuckerman Mind Brain Behaviour Institute

Jerome L. Greene Science Center

Columbia University

New York