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1.
Cell ; 187(6): 1476-1489.e21, 2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38401541

RESUMO

Attention filters sensory inputs to enhance task-relevant information. It is guided by an "attentional template" that represents the stimulus features that are currently relevant. To understand how the brain learns and uses templates, we trained monkeys to perform a visual search task that required them to repeatedly learn new attentional templates. Neural recordings found that templates were represented across the prefrontal and parietal cortex in a structured manner, such that perceptually neighboring templates had similar neural representations. When the task changed, a new attentional template was learned by incrementally shifting the template toward rewarded features. Finally, we found that attentional templates transformed stimulus features into a common value representation that allowed the same decision-making mechanisms to deploy attention, regardless of the identity of the template. Altogether, our results provide insight into the neural mechanisms by which the brain learns to control attention and how attention can be flexibly deployed across tasks.


Assuntos
Atenção , Tomada de Decisões , Aprendizagem , Lobo Parietal , Recompensa , Animais , Haplorrinos
2.
Cell ; 187(8): 1936-1954.e24, 2024 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-38490196

RESUMO

Microglia are brain-resident macrophages that shape neural circuit development and are implicated in neurodevelopmental diseases. Multiple microglial transcriptional states have been defined, but their functional significance is unclear. Here, we identify a type I interferon (IFN-I)-responsive microglial state in the developing somatosensory cortex (postnatal day 5) that is actively engulfing whole neurons. This population expands during cortical remodeling induced by partial whisker deprivation. Global or microglial-specific loss of the IFN-I receptor resulted in microglia with phagolysosomal dysfunction and an accumulation of neurons with nuclear DNA damage. IFN-I gain of function increased neuronal engulfment by microglia in both mouse and zebrafish and restricted the accumulation of DNA-damaged neurons. Finally, IFN-I deficiency resulted in excess cortical excitatory neurons and tactile hypersensitivity. These data define a role for neuron-engulfing microglia during a critical window of brain development and reveal homeostatic functions of a canonical antiviral signaling pathway in the brain.


Assuntos
Encéfalo , Interferon Tipo I , Microglia , Animais , Camundongos , Interferon Tipo I/metabolismo , Microglia/metabolismo , Neurônios/metabolismo , Peixe-Zebra , Encéfalo/citologia , Encéfalo/crescimento & desenvolvimento
3.
Cell ; 187(4): 962-980.e19, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38309258

RESUMO

Microglia (MG), the brain-resident macrophages, play major roles in health and disease via a diversity of cellular states. While embryonic MG display a large heterogeneity of cellular distribution and transcriptomic states, their functions remain poorly characterized. Here, we uncovered a role for MG in the maintenance of structural integrity at two fetal cortical boundaries. At these boundaries between structures that grow in distinct directions, embryonic MG accumulate, display a state resembling post-natal axon-tract-associated microglia (ATM) and prevent the progression of microcavities into large cavitary lesions, in part via a mechanism involving the ATM-factor Spp1. MG and Spp1 furthermore contribute to the rapid repair of lesions, collectively highlighting protective functions that preserve the fetal brain from physiological morphogenetic stress and injury. Our study thus highlights key major roles for embryonic MG and Spp1 in maintaining structural integrity during morphogenesis, with major implications for our understanding of MG functions and brain development.


Assuntos
Encéfalo , Microglia , Axônios , Encéfalo/citologia , Encéfalo/crescimento & desenvolvimento , Macrófagos/fisiologia , Microglia/patologia , Morfogênese
4.
Cell ; 187(2): 409-427.e19, 2024 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-38242086

RESUMO

Certain memories resist extinction to continue invigorating maladaptive actions. The robustness of these memories could depend on their widely distributed implementation across populations of neurons in multiple brain regions. However, how dispersed neuronal activities are collectively organized to underpin a persistent memory-guided behavior remains unknown. To investigate this, we simultaneously monitored the prefrontal cortex, nucleus accumbens, amygdala, hippocampus, and ventral tegmental area (VTA) of the mouse brain from initial recall to post-extinction renewal of a memory involving cocaine experience. We uncover a higher-order pattern of short-lived beta-frequency (15-25 Hz) activities that are transiently coordinated across these networks during memory retrieval. The output of a divergent pathway from upstream VTA glutamatergic neurons, paced by a slower (4-Hz) oscillation, actuates this multi-network beta-band coactivation; its closed-loop phase-informed suppression prevents renewal of cocaine-biased behavior. Binding brain-distributed neural activities in this temporally structured manner may constitute an organizational principle of robust memory expression.


Assuntos
Encéfalo , Memória , Animais , Camundongos , Tonsila do Cerebelo/fisiologia , Encéfalo/fisiologia , Cocaína/farmacologia , Cocaína/metabolismo , Memória/fisiologia , Córtex Pré-Frontal/fisiologia
5.
Cell ; 187(7): 1745-1761.e19, 2024 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-38518772

RESUMO

Proprioception tells the brain the state of the body based on distributed sensory neurons. Yet, the principles that govern proprioceptive processing are poorly understood. Here, we employ a task-driven modeling approach to investigate the neural code of proprioceptive neurons in cuneate nucleus (CN) and somatosensory cortex area 2 (S1). We simulated muscle spindle signals through musculoskeletal modeling and generated a large-scale movement repertoire to train neural networks based on 16 hypotheses, each representing different computational goals. We found that the emerging, task-optimized internal representations generalize from synthetic data to predict neural dynamics in CN and S1 of primates. Computational tasks that aim to predict the limb position and velocity were the best at predicting the neural activity in both areas. Since task optimization develops representations that better predict neural activity during active than passive movements, we postulate that neural activity in the CN and S1 is top-down modulated during goal-directed movements.


Assuntos
Neurônios , Propriocepção , Animais , Propriocepção/fisiologia , Neurônios/fisiologia , Encéfalo/fisiologia , Movimento/fisiologia , Primatas , Redes Neurais de Computação
6.
Cell ; 186(7): 1352-1368.e18, 2023 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-37001500

RESUMO

Resilience enables mental elasticity in individuals when rebounding from adversity. In this study, we identified a microcircuit and relevant molecular adaptations that play a role in natural resilience. We found that activation of parvalbumin (PV) interneurons in the primary auditory cortex (A1) by thalamic inputs from the ipsilateral medial geniculate body (MG) is essential for resilience in mice exposed to chronic social defeat stress. Early attacks during chronic social defeat stress induced short-term hyperpolarizations of MG neurons projecting to the A1 (MGA1 neurons) in resilient mice. In addition, this temporal neural plasticity of MGA1 neurons initiated synaptogenesis onto thalamic PV neurons via presynaptic BDNF-TrkB signaling in subsequent stress responses. Moreover, optogenetic mimicking of the short-term hyperpolarization of MGA1 neurons, rather than merely activating MGA1 neurons, elicited innate resilience mechanisms in response to stress and achieved sustained antidepressant-like effects in multiple animal models, representing a new strategy for targeted neuromodulation.


Assuntos
Córtex Auditivo , Camundongos , Animais , Córtex Auditivo/metabolismo , Tálamo/fisiologia , Neurônios/metabolismo , Corpos Geniculados , Interneurônios/fisiologia , Parvalbuminas/metabolismo
7.
Cell ; 186(17): 3726-3743.e24, 2023 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-37442136

RESUMO

Elucidating the cellular organization of the cerebral cortex is critical for understanding brain structure and function. Using large-scale single-nucleus RNA sequencing and spatial transcriptomic analysis of 143 macaque cortical regions, we obtained a comprehensive atlas of 264 transcriptome-defined cortical cell types and mapped their spatial distribution across the entire cortex. We characterized the cortical layer and region preferences of glutamatergic, GABAergic, and non-neuronal cell types, as well as regional differences in cell-type composition and neighborhood complexity. Notably, we discovered a relationship between the regional distribution of various cell types and the region's hierarchical level in the visual and somatosensory systems. Cross-species comparison of transcriptomic data from human, macaque, and mouse cortices further revealed primate-specific cell types that are enriched in layer 4, with their marker genes expressed in a region-dependent manner. Our data provide a cellular and molecular basis for understanding the evolution, development, aging, and pathogenesis of the primate brain.


Assuntos
Córtex Cerebral , Macaca , Análise de Célula Única , Transcriptoma , Animais , Humanos , Camundongos , Córtex Cerebral/citologia , Córtex Cerebral/metabolismo , Macaca/metabolismo , Transcriptoma/genética
8.
Cell ; 186(19): 4152-4171.e31, 2023 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-37669667

RESUMO

Social preference, the decision to interact with one member of the same species over another, is critical to optimize social interactions. Thus, adult rodents favor interacting with novel conspecifics over familiar ones, but whether this social preference stems from neural circuits facilitating interactions with novel individuals or suppressing interactions with familiar ones remains unknown. Here, we identify neurons in the infra-limbic area (ILA) of the mouse prefrontal cortex that express the neuropeptide corticotropin-releasing hormone (CRH) and project to the dorsal region of the rostral lateral septum (rLS). We show how release of CRH during familiar encounters disinhibits rLS neurons, thereby suppressing social interactions with familiar mice and contributing to social novelty preference. We further demonstrate how the maturation of CRH expression in ILA during the first 2 post-natal weeks enables the developmental shift from a preference for littermates in juveniles to a preference for novel mice in adults.


Assuntos
Hormônio Liberador da Corticotropina , Córtex Pré-Frontal , Animais , Camundongos , Neurônios , Transdução de Sinais , Percepção
9.
Cell ; 186(7): 1369-1381.e17, 2023 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-37001501

RESUMO

Memories initially formed in hippocampus gradually stabilize to cortex over weeks-to-months for long-term storage. The mechanistic details of this brain re-organization remain poorly understood. We recorded bulk neural activity in circuits that link hippocampus and cortex as mice performed a memory-guided virtual-reality task over weeks. We identified a prominent and sustained neural correlate of memory in anterior thalamus, whose inhibition substantially disrupted memory consolidation. More strikingly, gain amplification enhanced consolidation of otherwise unconsolidated memories. To gain mechanistic insights, we developed a technology for simultaneous cellular-resolution imaging of hippocampus, thalamus, and cortex throughout consolidation. We found that whereas hippocampus equally encodes multiple memories, the anteromedial thalamus preferentially encodes salient memories, and gradually increases correlations with cortex to facilitate tuning and synchronization of cortical ensembles. We thus identify a thalamo-cortical circuit that gates memory consolidation and propose a mechanism suitable for the selection and stabilization of hippocampal memories into longer-term cortical storage.


Assuntos
Consolidação da Memória , Memória de Longo Prazo , Camundongos , Animais , Memória de Longo Prazo/fisiologia , Tálamo/fisiologia , Hipocampo/fisiologia , Consolidação da Memória/fisiologia , Encéfalo
10.
Cell ; 186(1): 162-177.e18, 2023 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-36608651

RESUMO

The cortex influences movement by widespread top-down projections to many nervous system regions. Skilled forelimb movements require brainstem circuitry in the medulla; however, the logic of cortical interactions with these neurons remains unexplored. Here, we reveal a fine-grained anatomical and functional map between anterior cortex (AC) and medulla in mice. Distinct cortical regions generate three-dimensional synaptic columns tiling the lateral medulla, topographically matching the dorso-ventral positions of postsynaptic neurons tuned to distinct forelimb action phases. Although medial AC (MAC) terminates ventrally and connects to forelimb-reaching-tuned neurons and its silencing impairs reaching, lateral AC (LAC) influences dorsally positioned neurons tuned to food handling, and its silencing impairs handling. Cortico-medullary neurons also extend collaterals to other subcortical structures through a segregated channel interaction logic. Our findings reveal a precise alignment between cortical location, its function, and specific forelimb-action-tuned medulla neurons, thereby clarifying interaction principles between these two key structures and beyond.


Assuntos
Movimento , Neurônios , Camundongos , Animais , Movimento/fisiologia , Neurônios/fisiologia , Membro Anterior/fisiologia , Tronco Encefálico
11.
Cell ; 186(14): 3049-3061.e15, 2023 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-37311454

RESUMO

Membrane tension is thought to be a long-range integrator of cell physiology. Membrane tension has been proposed to enable cell polarity during migration through front-back coordination and long-range protrusion competition. These roles necessitate effective tension transmission across the cell. However, conflicting observations have left the field divided as to whether cell membranes support or resist tension propagation. This discrepancy likely originates from the use of exogenous forces that may not accurately mimic endogenous forces. We overcome this complication by leveraging optogenetics to directly control localized actin-based protrusions or actomyosin contractions while simultaneously monitoring the propagation of membrane tension using dual-trap optical tweezers. Surprisingly, actin-driven protrusions and actomyosin contractions both elicit rapid global membrane tension propagation, whereas forces applied to cell membranes alone do not. We present a simple unifying mechanical model in which mechanical forces that engage the actin cortex drive rapid, robust membrane tension propagation through long-range membrane flows.


Assuntos
Actinas , Actomiosina , Actinas/metabolismo , Actomiosina/metabolismo , Citoesqueleto de Actina/metabolismo , Membrana Celular/metabolismo , Movimento Celular/fisiologia
12.
Cell ; 186(20): 4438-4453.e23, 2023 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-37774681

RESUMO

Cellular perturbations underlying Alzheimer's disease (AD) are primarily studied in human postmortem samples and model organisms. Here, we generated a single-nucleus atlas from a rare cohort of cortical biopsies from living individuals with varying degrees of AD pathology. We next performed a systematic cross-disease and cross-species integrative analysis to identify a set of cell states that are specific to early AD pathology. These changes-which we refer to as the early cortical amyloid response-were prominent in neurons, wherein we identified a transitional hyperactive state preceding the loss of excitatory neurons, which we confirmed by acute slice physiology on independent biopsy specimens. Microglia overexpressing neuroinflammatory-related processes also expanded as AD pathology increased. Finally, both oligodendrocytes and pyramidal neurons upregulated genes associated with ß-amyloid production and processing during this early hyperactive phase. Our integrative analysis provides an organizing framework for targeting circuit dysfunction, neuroinflammation, and amyloid production early in AD pathogenesis.


Assuntos
Doença de Alzheimer , Lobo Frontal , Microglia , Neurônios , Humanos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Amiloide , Peptídeos beta-Amiloides/metabolismo , Microglia/patologia , Neurônios/patologia , Células Piramidais , Biópsia , Lobo Frontal/patologia , Análise da Expressão Gênica de Célula Única , Núcleo Celular/metabolismo , Núcleo Celular/patologia
13.
Cell ; 186(26): 5766-5783.e25, 2023 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-38134874

RESUMO

The enhanced cognitive abilities characterizing the human species result from specialized features of neurons and circuits. Here, we report that the hominid-specific gene LRRC37B encodes a receptor expressed in human cortical pyramidal neurons (CPNs) and selectively localized to the axon initial segment (AIS), the subcellular compartment triggering action potentials. Ectopic expression of LRRC37B in mouse CPNs in vivo leads to reduced intrinsic excitability, a distinctive feature of some classes of human CPNs. Molecularly, LRRC37B binds to the secreted ligand FGF13A and to the voltage-gated sodium channel (Nav) ß-subunit SCN1B. LRRC37B concentrates inhibitory effects of FGF13A on Nav channel function, thereby reducing excitability, specifically at the AIS level. Electrophysiological recordings in adult human cortical slices reveal lower neuronal excitability in human CPNs expressing LRRC37B. LRRC37B thus acts as a species-specific modifier of human neuron excitability, linking human genome and cell evolution, with important implications for human brain function and diseases.


Assuntos
Neurônios , Células Piramidais , Canais de Sódio Disparados por Voltagem , Animais , Humanos , Camundongos , Potenciais de Ação/fisiologia , Axônios/metabolismo , Neurônios/metabolismo , Canais de Sódio Disparados por Voltagem/genética , Canais de Sódio Disparados por Voltagem/metabolismo
14.
Cell ; 185(6): 1082-1100.e24, 2022 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-35216674

RESUMO

We assembled a semi-automated reconstruction of L2/3 mouse primary visual cortex from ∼250 × 140 × 90 µm3 of electron microscopic images, including pyramidal and non-pyramidal neurons, astrocytes, microglia, oligodendrocytes and precursors, pericytes, vasculature, nuclei, mitochondria, and synapses. Visual responses of a subset of pyramidal cells are included. The data are publicly available, along with tools for programmatic and three-dimensional interactive access. Brief vignettes illustrate the breadth of potential applications relating structure to function in cortical circuits and neuronal cell biology. Mitochondria and synapse organization are characterized as a function of path length from the soma. Pyramidal connectivity motif frequencies are predicted accurately using a configuration model of random graphs. Pyramidal cells receiving more connections from nearby cells exhibit stronger and more reliable visual responses. Sample code shows data access and analysis.


Assuntos
Neocórtex , Animais , Camundongos , Microscopia Eletrônica , Neocórtex/fisiologia , Organelas , Células Piramidais/fisiologia , Sinapses/fisiologia
15.
Cell ; 185(9): 1602-1617.e17, 2022 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-35487191

RESUMO

Prefrontal cortex (PFC) is postulated to exert "top-down control" on information processing throughout the brain to promote specific behaviors. However, pathways mediating top-down control remain poorly understood. In particular, knowledge about direct prefrontal connections that might facilitate top-down control of hippocampal information processing remains sparse. Here we describe monosynaptic long-range GABAergic projections from PFC to hippocampus. These preferentially inhibit vasoactive intestinal polypeptide-expressing interneurons, which are known to disinhibit hippocampal microcircuits. Indeed, stimulating prefrontal-hippocampal GABAergic projections increases hippocampal feedforward inhibition and reduces hippocampal activity in vivo. The net effect of these actions is to specifically enhance the signal-to-noise ratio for hippocampal encoding of object locations and augment object-induced increases in spatial information. Correspondingly, activating or inhibiting these projections promotes or suppresses object exploration, respectively. Together, these results elucidate a top-down prefrontal pathway in which long-range GABAergic projections target disinhibitory microcircuits, thereby enhancing signals and network dynamics underlying exploratory behavior.


Assuntos
Hipocampo , Córtex Pré-Frontal , Comportamento Exploratório , Hipocampo/fisiologia , Interneurônios/metabolismo , Córtex Pré-Frontal/fisiologia , Peptídeo Intestinal Vasoativo
16.
Cell ; 185(22): 4117-4134.e28, 2022 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-36306734

RESUMO

In most sensory modalities, neuronal connectivity reflects behaviorally relevant stimulus features, such as spatial location, orientation, and sound frequency. By contrast, the prevailing view in the olfactory cortex, based on the reconstruction of dozens of neurons, is that connectivity is random. Here, we used high-throughput sequencing-based neuroanatomical techniques to analyze the projections of 5,309 mouse olfactory bulb and 30,433 piriform cortex output neurons at single-cell resolution. Surprisingly, statistical analysis of this much larger dataset revealed that the olfactory cortex connectivity is spatially structured. Single olfactory bulb neurons targeting a particular location along the anterior-posterior axis of piriform cortex also project to matched, functionally distinct, extra-piriform targets. Moreover, single neurons from the targeted piriform locus also project to the same matched extra-piriform targets, forming triadic circuit motifs. Thus, as in other sensory modalities, olfactory information is routed at early stages of processing to functionally diverse targets in a coordinated manner.


Assuntos
Córtex Olfatório , Condutos Olfatórios , Camundongos , Animais , Bulbo Olfatório , Neurônios/fisiologia , Sequenciamento de Nucleotídeos em Larga Escala
17.
Cell ; 185(7): 1240-1256.e30, 2022 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-35305313

RESUMO

We developed a miniaturized two-photon microscope (MINI2P) for fast, high-resolution, multiplane calcium imaging of over 1,000 neurons at a time in freely moving mice. With a microscope weight below 3 g and a highly flexible connection cable, MINI2P allowed stable imaging with no impediment of behavior in a variety of assays compared to untethered, unimplanted animals. The improved cell yield was achieved through a optical system design featuring an enlarged field of view (FOV) and a microtunable lens with increased z-scanning range and speed that allows fast and stable imaging of multiple interleaved planes, as well as 3D functional imaging. Successive imaging across multiple, adjacent FOVs enabled recordings from more than 10,000 neurons in the same animal. Large-scale proof-of-principle data were obtained from cell populations in visual cortex, medial entorhinal cortex, and hippocampus, revealing spatial tuning of cells in all areas.


Assuntos
Cálcio , Córtex Visual , Animais , Córtex Entorrinal , Hipocampo , Camundongos , Microscopia , Neurônios/fisiologia
18.
Cell ; 185(2): 311-327.e24, 2022 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-35063073

RESUMO

The role of postnatal experience in sculpting cortical circuitry, while long appreciated, is poorly understood at the level of cell types. We explore this in the mouse primary visual cortex (V1) using single-nucleus RNA sequencing, visual deprivation, genetics, and functional imaging. We find that vision selectively drives the specification of glutamatergic cell types in upper layers (L) (L2/3/4), while deeper-layer glutamatergic, GABAergic, and non-neuronal cell types are established prior to eye opening. L2/3 cell types form an experience-dependent spatial continuum defined by the graded expression of ∼200 genes, including regulators of cell adhesion and synapse formation. One of these genes, Igsf9b, a vision-dependent gene encoding an inhibitory synaptic cell adhesion molecule, is required for the normal development of binocular responses in L2/3. In summary, vision preferentially regulates the development of upper-layer glutamatergic cell types through the regulation of cell-type-specific gene expression programs.


Assuntos
Visão Ocular , Córtex Visual/citologia , Córtex Visual/embriologia , Animais , Animais Recém-Nascidos , Biomarcadores/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Ácido Glutâmico/metabolismo , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/citologia , RNA-Seq , Transcriptoma/genética , Visão Binocular/genética , Ácido gama-Aminobutírico/metabolismo
19.
Cell ; 185(21): 3877-3895.e21, 2022 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-36152627

RESUMO

Williams-Beuren syndrome (WBS) is a rare disorder caused by hemizygous microdeletion of ∼27 contiguous genes. Despite neurodevelopmental and cognitive deficits, individuals with WBS have spared or enhanced musical and auditory abilities, potentially offering an insight into the genetic basis of auditory perception. Here, we report that the mouse models of WBS have innately enhanced frequency-discrimination acuity and improved frequency coding in the auditory cortex (ACx). Chemogenetic rescue showed frequency-discrimination hyperacuity is caused by hyperexcitable interneurons in the ACx. Haploinsufficiency of one WBS gene, Gtf2ird1, replicated WBS phenotypes by downregulating the neuropeptide receptor VIPR1. VIPR1 is reduced in the ACx of individuals with WBS and in the cerebral organoids derived from human induced pluripotent stem cells with the WBS microdeletion. Vipr1 deletion or overexpression in ACx interneurons mimicked or reversed, respectively, the cellular and behavioral phenotypes of WBS mice. Thus, the Gtf2ird1-Vipr1 mechanism in ACx interneurons may underlie the superior auditory acuity in WBS.


Assuntos
Córtex Auditivo/fisiologia , Síndrome de Williams/fisiopatologia , Animais , Córtex Auditivo/citologia , Modelos Animais de Doenças , Humanos , Células-Tronco Pluripotentes Induzidas , Interneurônios/citologia , Interneurônios/fisiologia , Camundongos , Fenótipo , Transativadores/genética , Síndrome de Williams/genética
20.
Cell ; 185(21): 3931-3949.e26, 2022 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-36240740

RESUMO

Neural migration is a critical step during brain development that requires the interactions of cell-surface guidance receptors. Cancer cells often hijack these mechanisms to disseminate. Here, we reveal crystal structures of Uncoordinated-5 receptor D (Unc5D) in complex with morphogen receptor glypican-3 (GPC3), forming an octameric glycoprotein complex. In the complex, four Unc5D molecules pack into an antiparallel bundle, flanked by four GPC3 molecules. Central glycan-glycan interactions are formed by N-linked glycans emanating from GPC3 (N241 in human) and C-mannosylated tryptophans of the Unc5D thrombospondin-like domains. MD simulations, mass spectrometry and structure-based mutants validate the crystallographic data. Anti-GPC3 nanobodies enhance or weaken Unc5-GPC3 binding and, together with mutant proteins, show that Unc5/GPC3 guide migrating pyramidal neurons in the mouse cortex, and cancer cells in an embryonic xenograft neuroblastoma model. The results demonstrate a conserved structural mechanism of cell guidance, where finely balanced Unc5-GPC3 interactions regulate cell migration.


Assuntos
Movimento Celular , Glipicanas/química , Receptores de Netrina/química , Animais , Glipicanas/metabolismo , Humanos , Camundongos , Proteínas Mutantes , Receptores de Netrina/metabolismo , Receptores de Superfície Celular/metabolismo , Anticorpos de Domínio Único , Trombospondinas
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