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Transcriptional Programming of Human Mechanosensory Neuron Subtypes from Pluripotent Stem Cells

ABSTRACT: In vitro generation of human peripheral sensory neurons may provide a framework for novel drug screening platforms and disease models of touch and pain. However, derivation of a functionally pure sensory neuron population remains a major unmet challenge. We discovered that, by expressing the transcription factors NGN2 and BRN3A, human pluripotent stem cells can be induced to differentiate into a surprisingly homogenous culture of cold- and mechano-sensing neurons. Although such a neuronal subtype has not been reported in mice, we found molecular evidence of its existence in adult human sensory ganglia. Combining NGN2 and BRN3A programming with neural crest patterning, we produced two additional populations of sensory neurons, including a more specialized mechanosensory neuron subtype. Finally, we applied this system to model a rare inherited sensory disorder, characterized by profound impairment of touch sensation and proprioception, caused by inactivating mutations in PIEZO2. Together these findings establish an approach to specify distinct sensory neuron subtypes in vitro, underscoring the utility of stem cell technology to capture human-specific features of physiology and disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE139273 | GEO | 2020/01/21

REPOSITORIES: GEO

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Transcriptional Programming of Human Mechanosensory Neuron Subtypes from Pluripotent Stem Cells

Project description:In vitro generation of human peripheral sensory neurons may provide a framework for novel drug screening platforms and disease models of touch and pain. However, derivation of a functionally pure sensory neuron population remains a major unmet challenge. We discovered that, by expressing the transcription factors NGN2 and BRN3A, human pluripotent stem cells can be induced to differentiate into a surprisingly homogenous culture of cold- and mechano-sensing neurons. Although such a neuronal subtype has not been reported in mice, we found molecular evidence of its existence in adult human sensory ganglia. Combining NGN2 and BRN3A programming with neural crest patterning, we produced two additional populations of sensory neurons, including a more specialized mechanosensory neuron subtype. Finally, we applied this system to model a rare inherited sensory disorder, characterized by profound impairment of touch sensation and proprioception, caused by inactivating mutations in PIEZO2. Together these findings establish an approach to specify distinct sensory neuron subtypes in vitro, underscoring the utility of stem cell technology to capture human-specific features of physiology and disease.

2019-12-31 | GSE139409 | GEO

Single-cell functional transcriptomics of mouse DRG mechanosensory neurons

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Project description:Mice lacking the POU-domain transcription factor Brn3a exhibit marked defects in sensory axon growth and abnormal sensory apoptosis. We have determined the regulatory targets of Brn3a in the developing trigeminal ganglion using microarray analysis of Brn3a mutant mice. These results show that Brn3 mediates the coordinated expression of neurotransmitter systems, ion channels, structural components of axons and inter- and intracellular signaling systems. Loss of Brn3a also results in the ectopic expression of transcription factors normally detected in earlier developmental stages and in other areas of the nervous system. Target gene expression is normal in heterozygous mice, consistent with prior work showing that autoregulation by Brn3a results in gene dosage compensation. Detailed examination of the expression of several of these downstream genes reveals that the regulatory role of Brn3a in the trigeminal ganglion appears to be conserved in more posterior sensory ganglia but not in the CNS neurons that express this factor. Experiment Overall Design: Microarrays used to compare the patterns of gene expression in the trigeminal ganglia of Brn3a knockout and wild-type mice. Embryonic day 13.5 (E13.5) was chosen because at this point in development mutant mice exhibit major defects in sensory axon growth, but have yet to undergo the period of extensive sensory neuron death associated with later stages.

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Transcription profiling of mouse dorsal root ganglion

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Ngn2 induces diverse neuronal lineages from human pluripotency

Project description:Human neurons engineered from induced pluripotent stem cells (iPSCs) through Neurogenin 2 (Ngn2) overexpression are widely used to study neuronal differentiation mechanisms and to model neurological diseases. However, the differentiation paths and heterogeneity of emerged neurons have not been fully explored. Here we used single-cell transcriptomics to dissect the cell states that emerge during Ngn2 overexpression across a time course from pluripotency to neuron functional maturation. We find a substantial molecular heterogeneity in the neuron types generated, with at least two populations that express genes associated with neurons of the peripheral nervous system. Neuron heterogeneity is observed across multiple iPSC clones and lines from different individuals. We find that neuron fate acquisition is sensitive to Ngn2 expression level and the duration of Ngn2 forced expression. Our data reveals that Ngn2 dosage can regulate neuron fate acquisition, and that Ngn2-iN heterogeneity can confound results that are sensitive to neuron type.

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Transcription profiling of mouse spinal and trigeminal sensory ganglia of Brn3a knockout and wild type mice reveals conserved and distinct regulatory targets of Brn3a at different levels of the sensory axis

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2008-06-14 | E-GEOD-5658 | biostudies-arrayexpress

Dorsal root ganglion (katz-affy-mouse-210210)

Project description:The molecular identity of touch sensation is still largely unknown. We choose an extrem and very specific example, touch sensation of pennis glan, to study this problem. It's known from previous retro-grade labeling result that only one DRG in rat innervate the pennis glan, which makes it idea for microarry analysis. To clone the mechanosensory receptor specifically or highly expressed in the primary sensory neurons innervating pennis glan. There is a specific mechanosensory receptor in the primary sensory neurons innervating pennis glan. 1. Retrograde labeling the innervating nerve by DiI 2. Dissect DRGs, dissociate neurons and pick up the fluorescent cells. 3. Pool around 20 positive cells and 50 control cells (big diameter neuron and small to medium diameter neuron respectively), purify total RNA. 4. Two rounds of amplification 5. Affymetrix analysis Keywords: dorsal root ganglion, touch sensatiion

2008-04-19 | GSE11207 | GEO

Differentiation of entire complement of spinal sensory interneurons from mouse embryonic stem cells (mESCs) [10X]

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