Adrenomedullin promotes the migration of interneurons in a human forebrain assembloid model for hypoxic interneuronopathy of prematurity.
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE183201 | GEO | 2023/09/01
REPOSITORIES: GEO
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Project description:Adrenomedullin promotes the migration of interneurons in a human forebrain assembloid model for hypoxic interneuronopathy of prematurity.
| PRJNA759605 | ENA
Project description:Since many years, we are interested in the regulation of the intraneuronal chloride concentration. We were the first group reporting a full knockout of the KCl-co-transporter KCC2, which dies immediately after birth due to respiratory failure. Notably, KCC2 loss-of-function mutations are associated with inherited febrile seizures, severe genetic generalized epilepsy and epilepsy of infancy with migrating focal seizures. Here, we used our floxed line to study the consequences of the disruption of KCC2 within parvalbumin-positive interneurons in mice. Remarkably, this leads to the disinhibition of PV-positive interneurons as evidenced by a decrease of E-S-Coupling and an increase in the sIPSC frequency. Nevertheless, these mice develop fatal epilepsy with progressive loss of parvalbumin-positive interneurons thus increasing network excitability.
2022-11-02 | E-MTAB-11147 | biostudies-arrayexpress
Project description:The embryonic basal ganglia generates multiple projection neurons and interneuron subtypes from distinct progenitor domains. Combinatorial interactions of transcription factors (TFs), regulatory elements (REs), and chromatin are thought to precisely regulate gene expression. In the medial ganglionic eminence (MGE), the NKX2-1 TF controls regional identity and, with LHX6, is necessary to specify pallidal projection neurons and forebrain interneurons. We dissected the molecular functions of NKX2-1 by defining its chromosomal binding regions, regulation of gene expression and epigenetic state. NKX2-1 binding at distal REs led to a repressed epigenetic state and transcriptional repression in the ventricular zone. Conversely, Nkx2-1 is required to establish a permissive chromatin state and transcriptional activation in the sub- ventricular and mantle zones. Moreover, combinatorial binding of NKX2-1 and LHX6 promotes transcriptionally permissive chromatin and activates genes expressed in cortical migrating interneurons. Our integrated approach provides a foundation for elucidating transcriptional networks guiding the development of the MGE and its descendants.
2016-09-21 | GSE85703 | GEO
Project description:The embryonic basal ganglia generates multiple projection neurons and interneuron subtypes from distinct progenitor domains. Combinatorial interactions of transcription factors (TFs), regulatory elements (REs), and chromatin are thought to precisely regulate gene expression. In the medial ganglionic eminence (MGE), the NKX2-1 TF controls regional identity and, with LHX6, is necessary to specify pallidal projection neurons and forebrain interneurons. We dissected the molecular functions of NKX2-1 by defining its chromosomal binding regions, regulation of gene expression and epigenetic state. NKX2-1 binding at distal REs led to a repressed epigenetic state and transcriptional repression in the ventricular zone. Conversely, Nkx2-1 is required to establish a permissive chromatin state and transcriptional activation in the sub- ventricular and mantle zones. Moreover, combinatorial binding of NKX2-1 and LHX6 promotes transcriptionally permissive chromatin and activates genes expressed in cortical migrating interneurons. Our integrated approach provides a foundation for elucidating transcriptional networks guiding the development of the MGE and its descendants.
2016-09-21 | GSE85704 | GEO
Project description:Decidual remodelling of midluteal endometrium leads to a short implantation window after which the uterine mucosa either breaks down or is transformed into a robust matrix that accommodates the placenta throughout pregnancy. To gain insights into the underlying mechanisms, we established and characterised endometrial assembloids, consisting of gland organoids and primary stromal cells. Single-cell transcriptomics revealed that decidualized assembloids closely resemble midluteal endometrium, harbouring differentiated and senescent subpopulations in both glands and stroma. We show that acute senescence in glandular epithelium drives secretion of multiple canonical implantation factors, whereas in the stroma it calibrates the emergence of anti-inflammatory decidual cells and pro-inflammatory senescent decidual cells. Pharmacological inhibition of stress responses in pre-decidual cells accelerated decidualization by inhibiting senescence and mesenchymal-epithelial transition, processes involved in endometrial breakdown and regeneration, respectively. Accelerated decidualization resulted in entrapment of co-cultured human blastocysts in a largely static decidual matrix. By contrast, the presence of senescent decidual cells created a dynamic implantation environment, enabling embryo expansion and attachment, although their persistence led to gradual disintegration of assembloids. Together, our findings demonstrate that senescence controls endometrial fate decisions at implantation and highlight how endometrial assembloids may accelerate the discovery of new treatments to prevent reproductive failure.
2021-03-08 | GSE168405 | GEO
Project description:Transplantation of GABAergic interneurons (INs) can sustain long-standing benefits in animal models of epilepsy and other neurological disorders. In a therapeutic perspective, a renewable source of functional GABAergic INs is needed. Here, we identified five factors (Foxg1, Sox2, Ascl1, Dlx5 and Lhx6) able to convert fibroblasts directly into induced GABAergic INs (iGABA-INs), displaying the molecular signature of telencephalic INs. The selected factors recapitulate in fibroblasts the activation of transcriptional networks required for the specification of GABAergic fate during telencephalon development. iGABA-INs exhibited progressively maturing firing patterns comparable to those of cortical INs, had synaptic currents and released GABA. Importantly, upon grafting in the hippocampus, iGABA-INs survived, matured and their optogenetic stimulation triggered GABAergic transmission and inhibited the activity of connected granule cells. The five factors also converted human cells into functional GABAergic neurons. These properties define iGABA-INs as a promising tool for disease modeling and cell-based therapeutic approaches. Comparison of iGABA-INs transcriptional profile with those of starting fibroblasts and GAD67-GFP+ cortical interneurons.
2015-12-15 | E-GEOD-74065 | biostudies-arrayexpress
Project description:In the mammalian cerebral cortex, the developmental events governing the allocation of different classes of inhibitory neurons into distinct cortical layers are poorly understood. Here we report that the guidance receptor PlexinA4 is upregulated in serotonin receptor 3a-expressing (HTR3A) cortical interneurons (hINs) as they invade the cortical plate and that it regulates their laminar allocation to superficial cortical layers. We find that the PlexinA4 ligand Semaphorin3A acts as a chemorepulsive factor on hINs migrating into the nascent cortex and demonstrate that Semaphorin3A specifically controls their laminar positioning through PlexinA4. We identify that deep layer interneurons constitute a major source of Semaphorin3A in the developing cortex and demonstrate that cell-type specific genetic deletion of Semaphorin3A in these interneurons specifically affects the laminar allocation of hINs. These data demonstrate that in the neocortex, deep layer interneurons control the laminar allocation of hINs into superficial layers.
2021-01-19 | GSE152271 | GEO
Project description:The patterns of synaptic connectivity and physiological properties of diverse neuron types are shaped by distinct gene sets. Our study demonstrates that, in the mouse forebrain, the transcriptional profiles of inhibitory GABAergic interneurons are regulated by Nr4a1, an orphan nuclear receptor whose expression is transiently induced by sensory experiences and is required for normal learning. Nr4a1 exerts contrasting effects on the local axonal wiring of Parvalbumin- and Somatostatin-positive interneurons, which innervate different subcellular domains of their postsynaptic partners. The loss of Nr4a1 activity in these interneurons results in bidirectional, cell-type-specific transcriptional switches across multiple gene families, including those involved in surface adhesion and repulsion. Our findings reveal that combinatorial synaptic organizing codes are surprisingly flexible and highlight a mechanism by which inducible transcription factors can influence neural circuit structure and function.
2024-06-05 | GSE263082 | GEO
Project description:Here we characterize the changes in the forebrain transcriptome resulting from the deletion of the transcription factor Lhx6, generated by RNA-seq technology with biologic replication. Lhx6 is an essential regulatory gene in the development of cortical interneurons generated in the medial ganglionic eminences of the embryonic brain. This data contains insights into gene networks important for the development of medial ganglionic eminence derived interneurons.
2017-12-16 | GSE108161 | GEO
Project description:Chronic stress is a major triggering factor for neuropsychiatric disorders including obsessive-compulsive disorder (OCD), a mental health condition characterized by motor stereotypies and striatal overactivation. However, the mechanisms at the cell- and microcircuit-level through which stress triggers motor symptoms is currently unknown. Here, we report that chronic stress (CS) in mice alters dorsomedial striatum (DMS) function, by affecting GABAergic interneuron populations and somatostatin-positive (SOM) interneurons in particular. Specifically, we show that CS impairs communication between SOM interneurons and medium spiny neurons, promoting striatal overactivation / disinhibition and increased motor output. Using probabilistic machine learning for analyzing animal behavior we further demonstrate that in vivo chemogenetic manipulation of SOM interneurons in DMS modulates motor phenotypes in stressed mice. Altogether, we propose a causal link between dysfunction of striatal SOM interneurons and motor symptoms in stress-related neuropsychiatric disorders.
2022-12-13 | PXD031193 | Pride