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Biology subjects

Curtis, A.

Publications and source records attributed to Curtis, A..

2 recordsLinked to original sources

A Spatiotemporal Map of Reading Aloud

Reading words aloud is a fundamental aspect of literacy. The rapid rate at which multiple distributed neural substrates are engaged in this process can only be probed via techniques with high spatiotemporal resolution. We probed this with direct intracranial recordings covering most of the left hemisphere in 46 humans as they read aloud regular, exception and pseudo-words. We used this to create a spatiotemporal map of word processing and to derive how broadband gamma activity varies with multiple word attributes critical to reading speed: lexicality, word frequency and orthographic neighborhood. We found that lexicality is encoded earliest in mid-fusiform (mFus) cortex and precentral sulcus, and is represented reliably enough to allow single-trial lexicality decoding. Word frequency is first represented in mFus and later in the inferior frontal gyrus (IFG) and inferior parietal sulcus (IPS), while orthographic neighborhood sensitivity resides solely in IPS. We thus isolate the neural correlates of the distributed reading network involving mFus, IFG, IPS, precentral sulcus and motor cortex and provide direct evidence for dual-route models of reading, with parallel processes via the lexical route from mFus to IFG, and the sub-lexical route from IPS and precentral sulcus to anterior IFG.

neuroscience

Inability to switch from ARID1A-BAF to ARID1B-BAF impairs exit from pluripotency and commitment towards neural crest differentiation in ARID1B-related neurodevelopmental disorders

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), which includes SMARCA4 and nine additional subunits. ARID1B-BAF acts as a gatekeeper, ensuring exit from pluripotency and lineage commitment, by attenuating NANOG, SOX2 and 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+), ARID1B-haploinsufficient CNCCs are also NANOG/OCT4-positive, in stark contrast with the ARID1B-wt CNCCs, which are NANOG/OCT4-negative. These findings suggest a connection between ARID1B mutations, neuroectoderm formation, and a pathogenic mechanism for Coffin-Siris syndrome.

genomics