Genetics and Epigenetics of the X and Y Chromosomes in the Sexual Differentiation of the Brain

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(20), P. 12288 - 12288

Published: Oct. 14, 2022

For many decades to date, neuroendocrinologists have delved into the key contribution of gonadal hormones generation sex differences in developing brain and expression sex-specific physiological behavioral phenotypes adulthood. However, it was not until recent years that role chromosomes matter started be seriously explored unveiled beyond determination. Now we know divergent evolutionary process suffered by X Y has determined they now encode mostly dissimilar genetic information are subject different epigenetic regulations, characteristics together contribute generate between XX XY cells/individuals from zygote throughout life. Here will review discuss relevant data showing how particular X- Y-linked genes mechanisms controlling their inheritance involved, along with or independently hormones, brain.

Language: Английский

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Chromosomal and gonadal factors regulate microglial sex effects in the aging brain

Brain Research Bulletin, Journal Year: 2023, Volume and Issue: 195, P. 157 - 171

Published: Feb. 15, 2023

Biological sex contributes to phenotypic effects through genetic (sex chromosomal) and hormonal (gonadal) mechanisms. There are profound differences in the prevalence progression of age-related brain diseases, including neurodegenerative diseases. Inflammation neural tissue is one most consistent phenotypes seen with healthy aging disease. The pro-inflammatory environment has primarily been attributed microglial reactivity adoption heterogeneous reactive states dependent upon intrinsic (i.e., sex) extrinsic age, disease state) factors. Here, we review microglia across lifespan, explore potential molecular mechanisms effects, discuss currently available models methods study brain. Despite recent attention this area, significant further research needed mechanistically understand regulation which may open new avenues for informed prevention treatment strategies.

Language: Английский

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Neurogenesis in primates versus rodents and the value of non-human primate models

National Science Review, Journal Year: 2023, Volume and Issue: 10(11)

Published: Sept. 15, 2023

ABSTRACT Neurogenesis, the process of generating neurons from neural stem cells, occurs during both embryonic and adult stages, with each stage possessing distinct characteristics. Dysfunction in either can disrupt normal development, impair cognitive functions, lead to various neurological disorders. Recent technological advancements single-cell multiomics gene-editing have facilitated investigations into primate neurogenesis. Here, we provide a comprehensive overview neurogenesis across rodents, non-human primates, humans, covering development adulthood focusing on conservation diversity among species. While especially monkeys, serve as valuable models closer resemblance highlight potential impacts limitations physiological pathological research.

Language: Английский

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Differential neurogenic patterns underlie the formation of primary and secondary areas in the developing somatosensory cortex

Cerebral Cortex, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 5, 2025

The cerebral cortex consists of hierarchically organized areas interconnected by reciprocal axonal projections. However, the coordination neurogenesis to optimize neuronal production and wiring between distinct cortical remains largely unexplored. somatosensory plays a crucial role in processing tactile information, with inputs from peripheral sensory receptors relayed through thalamus primary secondary areas. To investigate dynamics circuit formation, we employed temporal genetic fate mapping glutamatergic neuron cohorts across cortices. Our analysis revealed that (S2) precedes (S1) deep-layer period terminates earlier. We further progressive decline upper-layer output S2, attributed attenuation apical ventricular surface, resulting reduced number neurons within S2. These findings support existence protomap mechanism governing area-specific assembly developing neocortex.

Language: Английский

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Post-transcriptional cross- and auto-regulation buffer expression of the human RNA helicasesDDX3XandDDX3Y

Genome Research, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 10, 2025

The Y-linked gene DDX3Y and its X-linked homolog DDX3X survived the evolution of human sex chromosomes from ordinary autosomes. encodes a multifunctional RNA helicase, with mutations causing developmental disorders cancers. We find that, among genes surviving Y homologs, is extraordinarily dosage sensitive. Studying cells individuals chromosome aneuploidy, we observe that when number Chromosomes increases, transcript levels fall; conversely, X fall. In 46,XY cells, CRISPRi knockdown either or causes homologous to rise. 46,XX chemical inhibition protein activity elicits an increase in levels. Thus, perturbation expression buffered: by negative cross-regulation auto-regulation cells. – mediated through mRNA destabilization—as shown metabolic labeling newly transcribed RNA—and buffers total infer post-transcriptional ancestral (autosomal) transmuted into auto- as these sex-linked evolved alleles their autosomal precursor.

Language: Английский

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DEAD/DEAH-box RNA helicases shape the risk of neurodevelopmental disorders

Trends in Genetics, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

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Multi-modal investigation reveals pathogenic features of diverse DDX3X missense mutations

PLoS Genetics, Journal Year: 2025, Volume and Issue: 21(1), P. e1011555 - e1011555

Published: Jan. 21, 2025

De novo mutations in the RNA binding protein DDX3X cause neurodevelopmental disorders including syndrome and autism spectrum disorder. Amongst ~200 identified to date, half are missense. While loss of function is known impair neural cell fate, how landscape missense impacts neurodevelopment almost entirely unknown. Here, we integrate transcriptomics, proteomics, live imaging demonstrate clinically diverse perturb development via distinct cellular molecular mechanisms. Using mouse primary progenitors, investigate four recurrently mutated variants, spanning severe (2) mild (2). neurogenesis, have only a modest impact on fate. Moreover, expression leads profound neuronal death. proximity labeling screen discover variants unique interactors. We observe notable overlap amongst mutations, suggesting common mechanisms underlying altered fate survival. Transcriptomic analysis subsequent investigation highlights new pathways associated with upregulated DNA Damage Response. Notably, exhibit excessive damage neurons, increased cytoplasmic DNA:RNA hybrids formation stress granules. These findings highlight aberrant metabolism DDX3X-mediated In sum our reveal by which differentially neurodevelopment.

Language: Английский

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mRNA stability fine-tunes gene expression in the developing cortex to control neurogenesis

PLoS Biology, Journal Year: 2025, Volume and Issue: 23(2), P. e3003031 - e3003031

Published: Feb. 6, 2025

RNA abundance is controlled by rates of synthesis and degradation. Although mis-regulation turnover linked to neurodevelopmental disorders, how it contributes cortical development largely unknown. Here, we discover the landscape stability regulation in cerebral cortex demonstrate that intact decay machinery essential for corticogenesis vivo. We use SLAM-seq measure half-lives transcriptome-wide across multiple stages development. Leveraging these data, cis -acting features associated with probe relationship between half-life developmental expression changes. Notably, RNAs are up-regulated tend be more stable, while down-regulated less stable. Using compound mouse genetics, CNOT3, a core component CCR4-NOT deadenylase complex disease, Conditional knockout Cnot3 neural progenitors their progeny developing leads severe microcephaly due altered cell fate p53-dependent apoptosis. Finally, define molecular targets revealing controls poorly expressed, non-optimal mRNAs cortex, including cycle-related transcripts. Collectively, our findings fine-tuned control crucial brain

Language: Английский

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Diverse mechanisms of DDX3Y suppression by DDX3X

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 9, 2025

Abstract The DEAD-box RNA helicase DDX3X has important roles in development and disease. Loss of during developmental pathological processes such as tumorigenesis can lead to compensatory upregulation the close paralog DDX3Y males, which may underlie sexual dimorphism displayed by some DDX3X-associated diseases. However, how cross-regulates remains largely unknown. Here, we investigated regulation two male-derived human cancer cell lines, HCT116 U87MG. Depletion cells results moderately increased mRNA protein, part due stabilization transcripts. Conversely, reduction U87MG markedly upregulates protein without affecting its mRNA, mainly enhancing stability. We further show that physically interacts with DDX3Y. is much less stable than cells, substitution lysine residues corresponding arginine stabilizes Thus, following loss occur at either transcript or level, suggesting complex type-specific cross-regulation between these X- Y-linked paralogs keep total DDX3 dosage check.

Language: Английский

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A ubiquitous GC content signature underlies multimodal mRNA regulation by DDX3X

Molecular Systems Biology, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 25, 2024

The road from transcription to protein synthesis is paved with many obstacles, allowing for several modes of post-transcriptional regulation gene expression. A fundamental player in mRNA biology DDX3X, an RNA binding that canonically regulates translation. By monitoring dynamics abundance and translation following DDX3X depletion, we observe stabilization translationally suppressed mRNAs. We use interpretable statistical learning models uncover GC content the coding sequence as major feature underlying stabilization. This result corroborates content-related detectable other studies, including hundreds ENCODE datasets recent work focusing on cell cycle. provide further evidence by detailed analysis RNA-seq profiles samples, a Ddx3x conditional knockout mouse model exhibiting cycle neurogenesis defects. Our study identifies ubiquitous highlights importance quantifying multiple steps expression cascade, where production are often uncoupled.

Language: Английский

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