Androgens increase excitatory neurogenic potential in human brain organoids
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA777692 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR16767000.fastq.gz | Fastqsanger.gz | |||
| SRR16767001.fastq.gz | Fastqsanger.gz | |||
| SRR16767002.fastq.gz | Fastqsanger.gz | |||
| SRR16767003.fastq.gz | Fastqsanger.gz | |||
| SRR16767004.fastq.gz | Fastqsanger.gz |
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Project description:The biological basis of male-female brain differences has been difficult to elucidate in humans. The most striking morphological difference is size, with males having on average a larger brain than females; yet a mechanistic understanding of how this difference arises remains to be elucidated. Here, we use brain organoids to demonstrate that while sex chromosomal complement has no observable effect on neurogenesis, sex steroids, namely androgens, lead to increased proliferation of cortical progenitors and an increased neurogenic pool. Transcriptomic analysis and functional studies demonstrate downstream effects on HDAC activity and mTOR pathway. Finally, we show that androgens specifically increase neurogenic output of excitatory neuronal progenitors, while inhibitory neuronal progenitors are not increased. These findings uncover a hitherto unknown role for androgens in regulating excitatory neuron number and represent a first step towards understanding the origin of human sex-related brain differences.
2021-11-06 | GSE187877 | GEO
Project description:The biological basis of male-female brain differences has been difficult to elucidate in humans. The most notable morphological difference is size, with male individuals having on average a larger brain than female individuals1,2, but a mechanistic understanding of how this difference arises remains unknown. Here we use brain organoids3 to show that although sex chromosomal complement has no observable effect on neurogenesis, sex steroids-namely androgens-lead to increased proliferation of cortical progenitors and an increased neurogenic pool. Transcriptomic analysis and functional studies demonstrate downstream effects on histone deacetylase activity and the mTOR pathway. Finally, we show that androgens specifically increase the neurogenic output of excitatory neuronal progenitors, whereas inhibitory neuronal progenitors are not increased. These findings reveal a role for androgens in regulating the number of excitatory neurons and represent a step towards understanding the origin of sex-related brain differences in humans.
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Project description:A complex train of events unfolds during brain development, guided by activation/repression of gene expression programs. It remains unclear how this process is disrupted in disease. Here we integrate human genetics with transcriptomic data from differentiation of human embryonic stem cells into cortical excitatory neurons. This reveals a cascade of transcriptional programs activated during early corticoneurogenesis in vitro and in vivo. Genetic variation in these programs is robustly associated with neuropsychiatric disorders and cognitive function, with variants concentrated in loss-of-function intolerant genes. Neurogenic programs also capture schizophrenia GWAS enrichment previously identified in mature excitatory neurons, suggesting that pathways activated during pre-natal development underlie disease-relevant deficits in mature neuronal function. Down-regulation of these programs in DLG2-/- lines delays expression of cell-type identity and impairs neuronal migration, morphology and action potential generation, validating predicted deficits. These data implicate specific cellular pathways underlying neurodevelopment in the aetiology of multiple neuropsychiatric disorders and cognition.
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Project description:The proper balance of excitatory and inhibitory neurons is crucial to normal processing of somatosensory information in the dorsal spinal cord. Two neural basic helix-loop-helix transcription factors, Ascl1 and Ptf1a, are essential for generating the correct number and sub-type of neurons in multiple regions of the nervous system. M-BM- In the dorsal spinal cord, Ascl1 and Ptf1a have contrasting functions in specifying inhibitory versus excitatory neurons. To understand how Ascl1 and Ptf1a function in these processes, we identified their direct transcriptional targets genome-wide in the embryonic mouse neural tube using ChIP-Seq and RNA-Seq. We show that Ascl1 and Ptf1a regulate the specification of excitatory and inhibitory neurons in the dorsal spinal cord through direct regulation of distinct homeodomain transcription factors known for their function in neuronal sub-type specification. Besides their roles in regulating these homeodomain factors, Ascl1 and Ptf1a each function differently during neuronal development with Ascl1 directly regulating genes with roles in several steps of the neurogenic program including, Notch signaling, neuronal differentiation, axon guidance, and synapse formation. In contrast, Ptf1a directly regulates genes encoding components of the neurotransmitter machinery in inhibitory neurons, and other later aspects of neural development distinct from those regulated by Ascl1. Moreover, Ptf1a represses the excitatory neuronal fate by directly repressing several targets of Ascl1. Examination of the Ascl1 and Ptf1a bound sequences shows they are enriched for a common E-Box with a GC core and with additional motifs used by Sox, Rfx, Pou, and Homeodomain factors. Ptf1a bound sequences are uniquely enriched in an E-Box with a GA/TC core and in the binding motif for its co-factor Rbpj, providing two keys to specificity of Ptf1a binding. The direct transcriptional targets identified for Ascl1 and Ptf1a provide a molecular understanding for how they function in neuronal development, particularly as key regulators of homeodomain transcription factors required for neuronal sub-type specification. Examination of gene expression in Ascl1 and Ptf1a lineage cells in the developing neural tube.
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Project description:The proper balance of excitatory and inhibitory neurons is crucial to normal processing of somatosensory information in the dorsal spinal cord. Two neural basic helix-loop-helix transcription factors, Ascl1 and Ptf1a, are essential for generating the correct number and sub-type of neurons in multiple regions of the nervous system. M-BM- In the dorsal spinal cord, Ascl1 and Ptf1a have contrasting functions in specifying inhibitory versus excitatory neurons. To understand how Ascl1 and Ptf1a function in these processes, we identified their direct transcriptional targets genome-wide in the embryonic mouse neural tube using ChIP-Seq and RNA-Seq. We show that Ascl1 and Ptf1a regulate the specification of excitatory and inhibitory neurons in the dorsal spinal cord through direct regulation of distinct homeodomain transcription factors known for their function in neuronal sub-type specification. Besides their roles in regulating these homeodomain factors, Ascl1 and Ptf1a each function differently during neuronal development with Ascl1 directly regulating genes with roles in several steps of the neurogenic program including, Notch signaling, neuronal differentiation, axon guidance, and synapse formation. In contrast, Ptf1a directly regulates genes encoding components of the neurotransmitter machinery in inhibitory neurons, and other later aspects of neural development distinct from those regulated by Ascl1. Moreover, Ptf1a represses the excitatory neuronal fate by directly repressing several targets of Ascl1. Examination of the Ascl1 and Ptf1a bound sequences shows they are enriched for a common E-Box with a GC core and with additional motifs used by Sox, Rfx, Pou, and Homeodomain factors. Ptf1a bound sequences are uniquely enriched in an E-Box with a GA/TC core and in the binding motif for its co-factor Rbpj, providing two keys to specificity of Ptf1a binding. The direct transcriptional targets identified for Ascl1 and Ptf1a provide a molecular understanding for how they function in neuronal development, particularly as key regulators of homeodomain transcription factors required for neuronal sub-type specification. Examination of Ascl1 and Ptf1a genome-wide binding in developing neural tube.
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Project description:In the adult murine brain, neural stem cells (NSCs) reside in two main niches, the dentate gyrus (DG), and the subventricular zone (SVZ). In the DG, NSCs give rise to intermediate progenitors that differentiate into excitatory neurons, while progenitors in the SVZ migrate to the olfactory bulb (OB) where they mainly differentiate into inhibitory interneurons. Neurogenesis, the production of new neurons, persists throughout life but decrease dramatically during aging, concomitantly with increased inflammation. Many cell types, including microglia, undergo dramatic transcriptional changes but few such changes have been detected in neural progenitors. Furthermore, transcriptional profiles in progenitors from different neurogenic regions have not been compared at single cell level, and little is known about how they are affected by age-related inflammation. We have generated a single cell RNA sequencing dataset enriched for intermediate progenitors, which revealed that most aged neural progenitors only acquire minor transcriptional changes. However, progenitors set to become excitatory neurons decrease faster than others. In addition, a population in the aged SVZ, not detected in the OB, acquired major transcriptional activation related to immune responses. This suggests that differences in age related neurogenic decline between regions is not due to tissue differences but rather cell type specific intrinsic transcriptional programs, and that subset of neuroblasts in the SVZ react strongly to age related inflammatory cues.
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