Autism spectrum disorder (ASD) affects up to 1 in 59 individuals
. Genome-wide association and large-scale sequencing studies strongly implicate both common variants
and rare de novo variants
in ASD. ...Recessive mutations have also been implicated
but their contribution remains less well defined. Here we demonstrate an excess of biallelic loss-of-function and damaging missense mutations in a large ASD cohort, corresponding to approximately 5% of total cases, including 10% of females, consistent with a female protective effect. We document biallelic disruption of known or emerging recessive neurodevelopmental genes (CA2, DDHD1, NSUN2, PAH, RARB, ROGDI, SLC1A1, USH2A) as well as other genes not previously implicated in ASD including FEV (FEV transcription factor, ETS family member), which encodes a key regulator of the serotonergic circuitry. Our data refine estimates of the contribution of recessive mutation to ASD and suggest new paths for illuminating previously unknown biological pathways responsible for this condition.
It has long been hypothesized that aging and neurodegeneration are associated with somatic mutation in neurons; however, methodological hurdles have prevented testing this hypothesis directly. We ...used single-cell whole-genome sequencing to perform genome-wide somatic single-nucleotide variant (sSNV) identification on DNA from 161 single neurons from the prefrontal cortex and hippocampus of 15 normal individuals (aged 4 months to 82 years), as well as 9 individuals affected by early-onset neurodegeneration due to genetic disorders of DNA repair (Cockayne syndrome and xeroderma pigmentosum). sSNVs increased approximately linearly with age in both areas (with a higher rate in hippocampus) and were more abundant in neurodegenerative disease. The accumulation of somatic mutations with age-which we term genosenium-shows age-related, region-related, and disease-related molecular signatures and may be important in other human age-associated conditions.
Alternative splicing is prevalent in the mammalian brain. To interrogate the functional role of alternative splicing in neural development, we analyzed purified neural progenitor cells (NPCs) and ...neurons from developing cerebral cortices, revealing hundreds of differentially spliced exons that preferentially alter key protein domains—especially in cytoskeletal proteins—and can harbor disease-causing mutations. We show that Ptbp1 and Rbfox proteins antagonistically govern the NPC-to-neuron transition by regulating neuron-specific exons. Whereas Ptbp1 maintains apical progenitors partly through suppressing a poison exon of Flna in NPCs, Rbfox proteins promote neuronal differentiation by switching Ninein from a centrosomal splice form in NPCs to a non-centrosomal isoform in neurons. We further uncover an intronic human mutation within a PTBP1-binding site that disrupts normal skipping of the FLNA poison exon in NPCs and causes a brain-specific malformation. Our study indicates that dynamic control of alternative splicing governs cell fate in cerebral cortical development.
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•Alternative exons distinguish progenitors and neurons in developing cerebral cortex•Rbfox-mediated alternative splicing removes Ninein from centrosome for neurogenesis•An intronic mutation de-represses a FLNA poison exon, leading to brain malformation•Ptbp1 and Rbfox antagonistically regulate neuronal exon inclusion and neuronal fate
Moving beyond observation of widespread alternative splicing in the brain, regulated changes in alternative splicing patterns between neural progenitors and neurons are shown to drive cortical development in mice and humans.
Filamins were discovered as the first family of non-muscle actin-binding protein. They are lage cytoplasmic proteins that cross-link cortical actin into a dynamic three-dimensional structure. ...Filamins have also been reported to interact with a large number of cellular proteins of great functional diversity, suggesting that they are unusually versatile signalling scaffolds. More recently, genetic mutations in filamin A and B have been reported to cause a wide range of human diseases, suggesting that different diseases highlight distinct filamin interactions.
Significance
By evaluating children with a malformed cerebral cortex, we identified an ATPase pump (ATP1A3) with an early role in brain development. The ATP1A3 pump maintains the physiological ...concentration of sodium and potassium ions in cells, a process critical for osmotic equilibrium and membrane potential across several developing cell populations. We employed single-cell sequencing approaches to identify key enrichments for
ATP1A3
expression during human cortex development. Unravelling this early cell-type–specific pathophysiology in the developing brain offers a potential basis for the treatment of
ATP1A3
-related diseases affecting prenatal and early childhood development.
Osmotic equilibrium and membrane potential in animal cells depend on concentration gradients of sodium (Na
+
) and potassium (K
+
) ions across the plasma membrane, a function catalyzed by the Na
+
,K
+
-ATPase α-subunit. Here, we describe
ATP1A3
variants encoding dysfunctional α3-subunits in children affected by polymicrogyria, a developmental malformation of the cerebral cortex characterized by abnormal folding and laminar organization. To gain cell-biological insights into the spatiotemporal dynamics of prenatal
ATP1A3
expression, we built an
ATP1A3
transcriptional atlas of fetal cortical development using mRNA in situ hybridization and transcriptomic profiling of ∼125,000 individual cells with single-cell RNA sequencing (Drop-seq) from 11 areas of the midgestational human neocortex. We found that fetal expression of
ATP1A3
is most abundant to a subset of excitatory neurons carrying transcriptional signatures of the developing subplate, yet also maintains expression in nonneuronal cell populations. Moving forward a year in human development, we profiled ∼52,000 nuclei from four areas of an infant neocortex and show that
ATP1A3
expression persists throughout early postnatal development, most predominantly in inhibitory neurons, including parvalbumin interneurons in the frontal cortex. Finally, we discovered the heteromeric Na
+
,K
+
-ATPase pump complex may form nonredundant cell-type–specific α-β isoform combinations, including α3-β1 in excitatory neurons and α3-β2 in inhibitory neurons. Together, the developmental malformation phenotype of affected individuals and single-cell
ATP1A3
expression patterns point to a key role for α3 in human cortex development, as well as a cell-type basis for pre- and postnatal
ATP1A3
-associated diseases.
The epigenetic landscape is dynamically remodeled during neurogenesis. However, it is not understood how chromatin modifications in neural stem cells instruct the formation of complex structures in ...the brain. We report that the histone methyltransferase PRDM16 is required in radial glia to regulate lineage-autonomous and stage-specific gene expression programs that control number and position of upper layer cortical projection neurons. PRDM16 regulates the epigenetic state of transcriptional enhancers to activate genes involved in intermediate progenitor cell production and repress genes involved in cell migration. The histone methyltransferase domain of PRDM16 is necessary in radial glia to promote cortical neuron migration through transcriptional silencing. We show that repression of the gene encoding the E3 ubiquitin ligase PDZRN3 by PRDM16 determines the position of upper layer neurons. These findings provide insights into how epigenetic control of transcriptional enhancers in radial glial determines the organization of the mammalian cerebral cortex.
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•PRDM16 activity in radial glia encodes the number and position of cortical neurons•Enhancer regulation by PRDM16 represses neuronal migration genes in radial glia•PRDM16 controls neuron position by silencing the ubiquitin E3 ligase PDZRN3•The PR domain of PRDM16 promotes neuronal migration through gene silencing
Baizabal et al. uncover an epigenetic mechanism that encodes the number and position of upper layer cortical neurons in the activity of transcriptional enhancers in neural stem cells.
Somatic mutations arise postzygotically, producing genetic differences between cells in an organism. Well established as a driver of cancer, somatic mutations also exist in nonneoplastic cells, ...including in the brain. Technological advances in nucleic acid sequencing have enabled recent breakthroughs that illuminate the roles of somatic mutations in aging and degenerative diseases of the brain. Somatic mutations accumulate during aging in human neurons, a process termed genosenium. A number of recent studies have examined somatic mutations in Alzheimer's disease (AD), primarily from the perspective of genes causing familial AD. We have also gained new information on genome-wide mutations, providing insights into the cellular events driving somatic mutation and cellular dysfunction. This review highlights recent concepts, methods, and findings in the progress to understand the role of brain somatic mutation in aging and AD.
The unique size and complexity of the human cerebral cortex are achieved via a long and precisely regulated developmental process controlling neurogenesis, neuronal migration and differentiation. ...Traditionally, disorders of cortical development have been classified on the basis of the most obvious defects in one of these developmental steps. However, the more we learn about the cellular biological roles of genes that are essential for cortical development, the more we realize that these functions map onto molecular processes, but not so cleanly onto anatomical processes. Essential genes might be involved in both proliferation and migration as well as differentiation, reflecting roles for underlying molecular mechanisms in different phases of development and causing a stunning variety of cortical defects.
Neurosurgery elucidates somatic mutations Maury, Eduardo A; Walsh, Christopher A; Kahle, Kristopher T
Science (American Association for the Advancement of Science),
12/2023, Letnik:
382, Številka:
6677
Journal Article
Recenzirano
Surgical innovation is helping to identify roles for somatic mutations in brain disorders.
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