Reciprocal deletion and duplication of the 16p11.2 region is the most common copy number variation (CNV) associated with autism spectrum disorders. We generated cortical organoids from skin fibroblasts of patients with 16p11.2 CNV to investigate impacted neurodevelopmental processes. We show that organoid size recapitulates macrocephaly and microcephaly phenotypes observed in the patients with 16p11.2 deletions and duplications. The CNV dosage affects neuronal maturation, proliferation, and synapse number, in addition to its effect on organoid size. We demonstrate that 16p11.2 CNV alters the ratio of neurons to neural progenitors in organoids during early neurogenesis, with a significant excess of neurons and depletion of neural progenitors observed in deletions. Transcriptomic and proteomic profiling revealed multiple pathways dysregulated by the 16p11.2 CNV, including neuron migration, actin cytoskeleton, ion channel activity, synaptic-related functions, and Wnt signaling. The level of the active form of small GTPase RhoA was increased in both, deletions and duplications. Inhibition of RhoA activity rescued migration deficits, but not neurite outgrowth. This study provides insights into potential neurobiological mechanisms behind the 16p11.2 CNV during neocortical development.
E3-ubiquitin ligase Cullin3 (Cul3) is a high confidence risk gene for autism spectrum disorder (ASD) and developmental delay (DD). To investigate how Cul3 mutations impact brain development, we generated a haploinsufficient Cul3 mouse model using CRISPR/Cas9 genome engineering. Cul3 mutant mice exhibited social and cognitive deficits and hyperactive behavior. Brain MRI found decreased volume of cortical regions and changes in many other brain regions of Cul3 mutant mice starting from early postnatal development. Spatiotemporal transcriptomic and proteomic profiling of embryonic, early postnatal and adult brain implicated neurogenesis and cytoskeletal defects as key drivers of Cul3 functional impact. Specifically, dendritic growth, filamentous actin puncta, and spontaneous network activity were reduced in Cul3 mutant mice. Inhibition of small GTPase RhoA, a molecular substrate of Cul3 ligase, rescued dendrite length and network activity phenotypes. Our study identified defects in neuronal cytoskeleton and Rho signaling as the primary targets of Cul3 mutation during brain development.
Alternative splicing plays an important role in brain development. Chau et al. analyze the full-length isoform transcriptome of the developing brain and identify differentially expressed isoforms and isoform co-expression modules undetectable by gene-level analyses. They demonstrate that neurodevelopmental disease mutations affect different spicing isoforms, highlighting the importance of the isoform transcriptome for future studies.
SummaryReciprocal deletion and duplication of 16p11.2 is the most common copy number variation (CNV) associated with Autism Spectrum Disorders, and has significant effect on brain size. We generated cortical organoids to investigate neurodevelopmental pathways dysregulated by dosage changes of 16p11.2 CNV. We show that organoids recapitulate patients’ macrocephaly and microcephaly phenotypes. Deletions and duplications have “mirror” effects on cell proliferation, neuronal maturation and synapse number, consistent with “mirror” effects on brain development in humans. Excess neuron number along with depletion of neural progenitors in deletions, and “mirror” phenotypes in duplications, demonstrate dosage-dependent impact of 16p11.2 CNV on early neurogenesis. Transcriptomic and proteomic profiling revealed synaptic defects and neuron migration as key drivers of 16p11.2 functional effect. Treatment with the RhoA inhibitor Rhosin rescued neuron migration. We implicate upregulation of small GTPase RhoA as one of the pathways impacted by the 16p11.2 CNV. This study identifies pathways dysregulated by the 16p11.2 CNV during early neocortical development.
Rapid eye movement sleep (REMS) favors brain development and memory, while it is decreased in neurodegenerative diseases. REMS deprivation (REMSD) affects several physiological processes including memory consolidation; however, its detailed mechanism(s) of action was unknown. REMS reduces, while REMSD elevates noradrenaline (NA) level in the brain; the latter induces several deficiencies and disorders, including changes in neuronal cytomorphology and apoptosis. Therefore, we proposed that REMS‐ and REMSD‐associated modulation of NA level might affect neuronal plasticity and affect brain functions. Male albino rats were REMS deprived by flower‐pot method for 6 days, and its effects were compared with home cage and large platform controls as well as post‐REMSD recovered and REMS‐deprived prazosin (α1‐adrenoceptor antagonist)‐treated rats. We observed that REMSD reduced CA1 and CA3 neuronal dendritic length, branching, arborization, and spine density, while length of active zone and expressions of pre‐ as well as post‐synaptic proteins were increased as compared to controls; interestingly, prazosin prevented most of the effects in vivo. Studies on primary culture of neurons from chick embryo brain confirmed that NA at lower concentration(s) induced neuronal branching and arborization, while higher doses were destructive. The findings support our contention that REMSD adversely affects neuronal plasticity, branching, and synaptic scaffold, which explain the underlying cytoarchitectural basis of REMSD‐associated patho‐physio‐behavioral changes. Consolidation of findings of this study along with that of our previous reports suggest that the neuronal disintegration could be due to either withdrawal of direct protective and proliferative role of low dose of NA or indirect effect of high dose of NA or both.
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