8 research outputs found

    Genetic identification of brain cell types underlying schizophrenia

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    With few exceptions, the marked advances in knowledge about the genetic basis of schizophrenia have not converged on findings that can be confidently used for precise experimental modeling. By applying knowledge of the cellular taxonomy of the brain from single-cell RNA sequencing, we evaluated whether the genomic loci implicated in schizophrenia map onto specific brain cell types. We found that the common-variant genomic results consistently mapped to pyramidal cells, medium spiny neurons (MSNs) and certain interneurons, but far less consistently to embryonic, progenitor or glial cells. These enrichments were due to sets of genes that were specifically expressed in each of these cell types. We also found that many of the diverse gene sets previously associated with schizophrenia (genes involved in synaptic function, those encoding mRNAs that interact with FMRP, antipsychotic targets, etc.) generally implicated the same brain cell types. Our results suggest a parsimonious explanation: the common-variant genetic results for schizophrenia point at a limited set of neurons, and the gene sets point to the same cells. The genetic risk associated with MSNs did not overlap with that of glutamatergic pyramidal cells and interneurons, suggesting that different cell types have biologically distinct roles in schizophrenia

    Genetic identification of brain cell types underlying schizophrenia

    Get PDF
    With few exceptions, the marked advances in knowledge about the genetic basis of schizophrenia have not converged on findings that can be confidently used for precise experimental modeling. Applying knowledge of the cellular taxonomy of the brain from single-cell RNA-sequencing, we evaluated whether the genomic loci implicated in schizophrenia map onto specific brain cell types. We found that the common variant genomic results consistently mapped to pyramidal cells, medium spiny neurons, and certain interneurons but far less consistently to embryonic, progenitor, or glial cells. These enrichments were due to sets of genes specifically expressed in each of these cell types. We also found that many of the diverse gene sets previously associated with schizophrenia (synaptic genes, FMRP interactors, antipsychotic targets, etc.) generally implicate the same brain cell types. Our results suggest a parsimonious explanation: the common-variant genetic results for schizophrenia point at a limited set of neurons, and the gene sets point to the same cells. The genetic risk associated with medium spiny neurons did not overlap with that of glutamatergic pyramidal cells and interneurons, suggesting that different cell types have biologically distinct roles in schizophrenia

    The Runx1/AML1 transcription factor selectively regulates development and survival of TrkA nociceptive sensory neurons

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    Neural crest cells (NCCs) can adopt different neuronal fates. In NCCs, neurogenin-2 promotes sensory specification but does not specify different subclasses of sensory neurons. Understanding the gene cascades that direct Trk gene activation may reveal mechanisms generating sensory diversity, because different Trks are expressed in different sensory neuron subpopulations. Here we show in chick and mouse that the Runt transcription factor Runx1 promotes axonal growth, is selectively expressed in neural crest-derived TrkA(+) sensory neurons and mediates TrkA transactivation in migratory NCCs. Inhibition of Runt activity depletes TrkA expression and leads to neuronal death. Moreover, Runx1 overexpression is incompatible with multipotency in the migratory neural crest but does not induce expression of pan-neuronal genes. Instead, Runx1-induced neuronal differentiation depends on an existing neurogenin2 proneural gene program. Our data show that Runx1 directs, in a context-dependent manner, key aspects of the establishment of the TrkA(+) nociceptive subclass of neurons

    Neurotrophin Signalling and Transcription Programmes Interactions in the Development of Somatosensory Neurons

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    TRPV4: a Sensor for Homeostasis and Pathological Events in the CNS

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    FACS-Seq analysis of Pax3-derived cells identifies non-myogenic lineages in the embryonic forelimb

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