Le récepteur nucléaire orphelin COUP-TFI contrôle l’identité sensorielle et l'activité neuronale dans les cellules post-mitotiques du néocortex chez la souris

The neocortex is a region of the brain that processes all sensory inputs creating appropriate behavioral responses. It is subdivided into functional areas, each with a specific cytoarchitecture, gene expression pattern and connectivity profile. The organization into areas is pre-patterned by the action of areal patterning genes, and subsequently refined by sensory evoked activity. In this study, I have first investigated whether early areal patterning is committed in progenitor and/or post-mitotic cells, and then assessed whether spontaneous neuronal activity is required in establishing correct connectivity between the neocortex and the thalamus, the principal relay station of peripheral sensory inputs. With the help of a series of transgenic mice, my work showed that the function of the areal patterning gene COUP-TFI is sufficient and necessary to organize sensory identity in post-mitotic cells, and that COUP-TFI regulates intrinsic activity properties of cortical neurons, and thus proper integration of thalamic inputs into the somatosensory cortex. In particular, I found that COUP-TFI directly controls the expression of the immediate early gene Egr1, which expression levels strongly depend on neuronal activity. Both COUP-TFI and Egr1 act on the acquisition of the stellate cell morphology of layer 4 neurons, the main targets of thalamic axons and a typical trait of primary somatosensory areas. In conclusion, this work demonstrates that cortical area patterning primordially depends on a genetic program established in post-mitotic cells and that intrinsic genetic and activity properties act together to shape the organization of early circuits in the neocortex.Le néocortex est une région du cerveau qui traite toutes les entrées sensorielles et créé des réponses comportementales. Il est subdivisé en zones fonctionnelles, chacune ayant une cytoarchitecture, un motif d’expression génique et un profil de connectivité spécifiques. L'organisation en zones est pré-modelée par des gènes organisateurs, et ensuite affinée par l’activité sensorielle. Dans cette étude, j'ai étudié d'abord si ce pré-modelage est établi dans les progéniteurs et/ou les cellules post-mitotiques, et si l'activité neuronale spontanée est nécessaire pour l’établissement de la connectivité correcte entre néocortex et thalamus, station relais principale des données sensorielles. Avec l'aide d'une série de souris transgéniques, j’ai montré que la fonction du gène organisateur COUP-TFI est suffisante et nécessaire pour organiser l'identité sensorielle dans les cellules post-mitotiques, et que COUP-TFI régule l'activité intrinsèque des neurones corticaux, influençant la bonne intégration des entrées thalamiques dans le cortex somatosensoriel. J’ai montré que COUP-TFI contrôle directement l'expression du gène Egr1, qui dépend fortement de l'activité neuronale. COUP-TFI et Egr1 agissent sur l'acquisition de la morphologie des cellules étoilées dans les neurones de la couche 4, cibles principales des axones thalamiques et trait typique des zones somatosensoriels primaires. En conclusion, ce travail montre que le pré-modelage cortical dépend primordialement d’un programme génétique établi dans les cellules post-mitotiques et que l'activité intrinsèque et les propriétés génétiques agissent ensemble pour façonner l'organisation des premiers circuits dans le néocortex

The orphan nuclear receptor COUP-TFI controls sensory identity and neuronal activity in post-mitotic cells of the mouse neocortex

Le néocortex est une région du cerveau qui traite toutes les entrées sensorielles et créé des réponses comportementales. Il est subdivisé en zones fonctionnelles, chacune ayant une cytoarchitecture, un motif d’expression génique et un profil de connectivité spécifiques. L'organisation en zones est pré-modelée par des gènes organisateurs, et ensuite affinée par l’activité sensorielle. Dans cette étude, j'ai étudié d'abord si ce pré-modelage est établi dans les progéniteurs et/ou les cellules post-mitotiques, et si l'activité neuronale spontanée est nécessaire pour l’établissement de la connectivité correcte entre néocortex et thalamus, station relais principale des données sensorielles. Avec l'aide d'une série de souris transgéniques, j’ai montré que la fonction du gène organisateur COUP-TFI est suffisante et nécessaire pour organiser l'identité sensorielle dans les cellules post-mitotiques, et que COUP-TFI régule l'activité intrinsèque des neurones corticaux, influençant la bonne intégration des entrées thalamiques dans le cortex somatosensoriel. J’ai montré que COUP-TFI contrôle directement l'expression du gène Egr1, qui dépend fortement de l'activité neuronale. COUP-TFI et Egr1 agissent sur l'acquisition de la morphologie des cellules étoilées dans les neurones de la couche 4, cibles principales des axones thalamiques et trait typique des zones somatosensoriels primaires. En conclusion, ce travail montre que le pré-modelage cortical dépend primordialement d’un programme génétique établi dans les cellules post-mitotiques et que l'activité intrinsèque et les propriétés génétiques agissent ensemble pour façonner l'organisation des premiers circuits dans le néocortex.The neocortex is a region of the brain that processes all sensory inputs creating appropriate behavioral responses. It is subdivided into functional areas, each with a specific cytoarchitecture, gene expression pattern and connectivity profile. The organization into areas is pre-patterned by the action of areal patterning genes, and subsequently refined by sensory evoked activity. In this study, I have first investigated whether early areal patterning is committed in progenitor and/or post-mitotic cells, and then assessed whether spontaneous neuronal activity is required in establishing correct connectivity between the neocortex and the thalamus, the principal relay station of peripheral sensory inputs. With the help of a series of transgenic mice, my work showed that the function of the areal patterning gene COUP-TFI is sufficient and necessary to organize sensory identity in post-mitotic cells, and that COUP-TFI regulates intrinsic activity properties of cortical neurons, and thus proper integration of thalamic inputs into the somatosensory cortex. In particular, I found that COUP-TFI directly controls the expression of the immediate early gene Egr1, which expression levels strongly depend on neuronal activity. Both COUP-TFI and Egr1 act on the acquisition of the stellate cell morphology of layer 4 neurons, the main targets of thalamic axons and a typical trait of primary somatosensory areas. In conclusion, this work demonstrates that cortical area patterning primordially depends on a genetic program established in post-mitotic cells and that intrinsic genetic and activity properties act together to shape the organization of early circuits in the neocortex

Heterogeneous fates of simultaneously-born neurons in the cortical ventricular zone

Neocortical excitatory neurons belong to diverse cell types, which can be distinguished by their dates of birth, laminar location, connectivity, and molecular identities. During embryogenesis, apical progenitors (APs) located in the ventricular zone first give birth to deep-layer neurons, and next to superficial-layer neurons. While the overall sequential construction of neocortical layers is well-established, whether APs produce multiple neuron types at single time points of corticogenesis is unknown. To address this question, here we used FlashTag to fate-map simultaneously-born (i.e. isochronic) cohorts of AP daughter neurons at successive stages of corticogenesis. We reveal that early in corticogenesis, isochronic neurons differentiate into heterogeneous laminar, hodological and molecular cell types. Later on, instead, simultaneously-born neurons have more homogeneous fates. Using single-cell gene expression analyses, we identify an early postmitotic surge in the molecular heterogeneity of nascent neurons during which some early-born neurons initiate and partially execute late-born neuron transcriptional programs. Together, these findings suggest that as corticogenesis unfolds, mechanisms allowing increased homogeneity in neuronal output are progressively implemented, resulting in progressively more predictable neuronal identities

Inhibition of Trpv4 rescues circuit and social deficits unmasked by acute inflammatory response in a Shank3 mouse model of Autism

Mutations in the SHANK3 gene have been recognized as a genetic risk factor for Autism Spectrum Disorder (ASD), a neurodevelopmental disease characterized by social deficits and repetitive behaviors. While heterozygous SHANK3 mutations are usually the types of mutations associated with idiopathic autism in patients, heterozygous deletion of Shank3 gene in mice does not commonly induce ASD-related behavioral deficit. Here, we used in-vivo and ex-vivo approaches to demonstrate that region-specific neonatal downregulation of Shank3 in the Nucleus Accumbens promotes D1R-medium spiny neurons (D1R-MSNs) hyperexcitability and upregulates Transient Receptor Potential Vanilloid 4 (Trpv4) to impair social behavior. Interestingly, genetically vulnerable Shank3+/-mice, when challenged with Lipopolysaccharide to induce an acute inflammatory response, showed similar circuit and behavioral alterations that were rescued by acute Trpv4 inhibition. Altogether our data demonstrate shared molecular and circuit mechanisms between ASD-relevant genetic alterations and environmental insults, which ultimately lead to sociability dysfunctions

COUP-TFI/Nr2f1 Orchestrates Intrinsic Neuronal Activity during Development of the Somatosensory Cortex

International audienceThe formation of functional cortical maps in the cerebral cortex results from a timely regulated interaction between intrinsic genetic mechanisms and electrical activity. To understand how transcriptional regulation influences network activity and neuronal excitability within the neocortex, we used mice deficient for Nr2f1 (also known as COUP-TFI), a key determinant of primary somatosensory (S1) area specification during development. We found that the cortical loss of Nr2f1 impacts on spontaneous network activity and synchronization of S1 cortex at perinatal stages. In addition, we observed alterations in the intrinsic excitability and morphological features of layer V pyramidal neurons. Accordingly, we identified distinct voltage-gated ion channels regulated by Nr2f1 that might directly influence intrinsic bioelectrical properties during critical time windows of S1 cortex specification. Altogether, our data suggest a tight link between Nr2f1 and neuronal excitability in the developmental sequence that ultimately sculpts the emergence of cortical network activity within the immature neocortex

Area-specific development of distinct projection neuron subclasses is regulated by postnatal epigenetic modifications

International audienceDuring cortical development, the identity of major classes of long-distance projection neurons is established by the expression of molecular determinants, which become gradually restricted and mutually exclusive. However, the mechanisms by which projection neurons acquire their final properties during postnatal stages are still poorly understood. In this study, we show that the number of neurons co-expressing Ctip2 and Satb2, respectively involved in the early specification of subcerebral and callosal projection neurons, progressively increases after birth in the somatosensory cortex. Ctip2/Satb2 postnatal co-localization defines two distinct neuronal subclasses projecting either to the contralateral cortex or to the brainstem suggesting that Ctip2/ Satb2 co-expression may refine their properties rather than determine their identity. Gain-and loss-of-function approaches reveal that the transcriptional adaptor Lmo4 drives this maturation program through modulation of epigenetic mechanisms in a time-and area-specific manner, thereby indicating that a previously unknown genetic program postnatally promotes the acquisition of final subtype-specific features

A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease

The mediator (MED) multisubunit-complex modulates the activity of the transcriptional machinery, and genetic defects in different MED subunits (17, 20, 27) have been implicated in neurologic diseases. In this study, we identified a recurrent homozygous variant in MED11 (c.325C>T; p.Arg109Ter) in 7 affected individuals from 5 unrelated families