ARID1B controls transcriptional programs of axon projection in an organoid model of the human corpus callosum
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE231546 | GEO | 2023/12/01
REPOSITORIES: GEO
Similar Datasets
Project description:ARID1B controls transcriptional programs of axon projection in an organoid model of the human corpus callosum
| PRJNA966891 | ENA
Project description:How developing axons in the corpus callosum (CC) achieve their homotopic projection to the contralateral cortex remains unclear. We found that axonal position within the CC plays a critical role in this projection. Labeling of nearby callosal axons in mice showed that callosal axons were segregated in an orderly fashion, with those from more medial cerebral cortex located more dorsally and subsequently projecting to more medial contralateral cortical regions. The normal axonal order within the CC was grossly disturbed when semaphorin3A/neuropilin-1 signaling was disrupted. However, the order in which axons were positioned within the CC still determined their contralateral projection, causing a severe disruption of the homotopic contralateral projection that persisted at postnatal day 30, when the normal developmental refinement of contralateral projections is completed in wild-type (WT) mice. Thus, the orderly positioning of axons within the CC is a primary determinant of how homotopic interhemispheric projections form in the contralateral cortex.
| S-EPMC3718183 | biostudies-literature
Project description:Axon diameter is an important neuroanatomical characteristic of the nervous system that alters in the course of neurological disorders such as multiple sclerosis. Axon diameters vary, even within a fiber bundle, and are not normally distributed. An accurate distribution function is therefore beneficial, either to describe axon diameters that are obtained from a direct measurement technique (e.g., microscopy), or to infer them indirectly (e.g., using diffusion-weighted MRI). The gamma distribution is a common choice for this purpose (particularly for the inferential approach) because it resembles the distribution profile of measured axon diameters which has been consistently shown to be non-negative and right-skewed. In this study we compared a wide range of parametric probability distribution functions against empirical data obtained from electron microscopy images. We observed that the gamma distribution fails to accurately describe the main characteristics of the axon diameter distribution, such as location and scale of the mode and the profile of distribution tails. We also found that the generalized extreme value distribution consistently fitted the measured distribution better than other distribution functions. This suggests that there may be distinct subpopulations of axons in the corpus callosum, each with their own distribution profiles. In addition, we observed that several other distributions outperformed the gamma distribution, yet had the same number of unknown parameters; these were the inverse Gaussian, log normal, log logistic and Birnbaum-Saunders distributions.
| S-EPMC4880597 | biostudies-literature
Project description:Corpus callosum abnormalities, intellectual disability, speech impairment, and autism in patients with haploinsufficiency of ARID1B. Corpus callosum abnormalities are common brain malformations with a wide clinical spectrum ranging from severe intellectual disability to normal cognitive function. The etiology is expected to be genetic in as much as 30-50% of the cases, but the underlying genetic cause remains unknown in the majority of cases. By next-generation mate-pair sequencing we mapped the chromosomal breakpoints of a patient with a de novo balanced translocation, t(1;6)(p31;q25), agenesis of corpus callosum (CC), intellectual disability, severe speech impairment, and autism. The chromosome 6 breakpoint truncated ARID1B which was also truncated in a recently published translocation patient with a similar phenotype. Quantitative polymerase chain reaction (Q-PCR) data showed that a primer set proximal to the translocation showed increased expression of ARID1B, whereas primer sets spanning or distal to the translocation showed decreased expression in the patient relative to a non-related control set. Phenotype-genotype comparison of the translocation patient to seven unpublished patients with various sized deletions encompassing ARID1B confirms that haploinsufficiency of ARID1B is associated with CC abnormalities, intellectual disability, severe speech impairment, and autism. Our findings emphasize that ARID1B is important in human brain development and function in general, and in the development of CC and in speech development in particular.
| S-EPMC3464360 | biostudies-literature
Project description:The BAF complex modulates chromatin accessibility. Specific BAF configurations have functional consequences, and subunit switches are essential for cell differentiation. ARID1B and its paralog ARID1A encode for mutually exclusive BAF subunits. De novo ARID1B haploinsufficient mutations cause a neurodevelopmental disorder spectrum, including Coffin-Siris syndrome, which is characterized by neurological and craniofacial features. Here, we reprogrammed ARID1B+/- Coffin-Siris patient-derived skin fibroblasts into iPSCs, and modeled cranial neural crest cell (CNCC) formation. We discovered that ARID1B is active only during the first stage of this process, coinciding with neuroectoderm specification, where it is part of a lineage-specific BAF configuration (ARID1B-BAF), including SMARCA4, and nine additional subunits. ARID1B-BAF acts as a gate-keeper, ensuring exit from pluripotency and lineage commitment, by attenuating NANOG, SOX2 and the thousands of enhancers directly regulated by these two pluripotency factors at the iPSC stage. In iPSCs, these enhancers are maintained active by an ARID1A-containing BAF. At the onset of differentiation, cells transition from ARID1A-BAF to ARID1B-BAF, eliciting attenuation of the NANOG/SOX2 networks, and triggering pluripotency exit. Coffin-Siris patient cells fail to perform the ARID1A/ARID1B switch, and maintain ARID1A-BAF at pluripotency enhancers throughout all stages of CNCC formation. This leads to a persistent and aberrant SOX2 and NANOG activity, which impairs CNCC formation. In fact, despite showing the typical neural crest signature (TFAP2A+, SOX9+), the ARID1B-haploinsufficient CNCCs are also NANOG-positive, in stark contrast with the ARID1B-wt CNCCs, which are NANOG-negative. These findings suggest a connection between ARID1B mutations, neuroectoderm formation, and a pathogenic mechanism for Coffin-Siris syndrome.
2021-10-12 | PXD028557 | Pride
Project description:One of the earliest steps during the development of the nervous system is the establishment of neuronal polarity and the formation of an axon. The intrinsic mechanisms that promote axon formation have been extensively analyzed. However, much less is known about the extrinsic signals that initiate axon formation. One of the candidates for these signals is Insulin-like growth factor 1 (Igf1) that acts through the Igf1 (Igf1R) and insulin receptors (InsR). Since Igf1R and InsR may act redundantly we analyzed conditional cortex-specific knockout mice that are deficient for both Igf1r and Insr to determine if they regulate the development of the cortex and the formation of axons in vivo. Our results show that Igf1R/InsR function is required for the normal development of the embryonic hippocampus and cingulate cortex while the lateral cortex does not show apparent defects in the Igf1r;Insr knockout. In the cingulate cortex, the number of intermediate progenitors and deep layer neurons is reduced and the corpus callosum is absent at E17. However, cortical organization and axon formation are not impaired in knockout embryos. In culture, cortical and hippocampal neurons from Igf1r;Insr knockout embryos extend an axon but the length of this axon is severely reduced. Our results indicate that Igf1R/InsR function is required for brain development in a region-specific manner and promotes axon growth but is not essential for neuronal polarization and migration in the developing brain.
| S-EPMC6638864 | biostudies-literature
Project description:We transduced either an empty vector or ARID1B cDNA in IMR90 cells. Cells were selected with puromycin and 6 days after the infection we collected the RNA. ARID1B is a member of the SWI/SNF chromatin-remodeling complex. Our previous experiments showed that knockdown of ARID1B allows cells to bypass cellular senescence. By performing RNA-seq we have shown that ARID1B expression can induce a set of genes involved in the senescence response.
2016-11-12 | GSE75291 | GEO