Biology subjects

Martins-Costa, C.

Publications and source records attributed to Martins-Costa, C..

3 recordsLinked to original sources

bioRxiv2023

ARID1B controls transcriptional programs of axon projection in the human corpus callosum

Mutations in ARID1B, a member of the mSWI/SNF complex, cause severe neurodevelopmental phenotypes with elusive mechanisms in humans. The most common structural abnormality in the brain of ARID1B patients is agenesis of the corpus callosum (ACC). This condition is characterized by a partial or complete absence of the corpus callosum (CC), an interhemispheric white matter tract that connects distant cortical regions. Using human neural organoids, we identify a vulnerability of callosal projection neurons (CPNs) to ARID1B haploinsufficiency, resulting in abnormal maturation trajectories and dysregulation of transcriptional programs of CC development. Through a novel in vitro model of the CC tract, we demonstrate that ARID1B mutations reduce the proportion of CPNs capable of forming long-range projections, leading to structural underconnectivity phenotypes. Our study uncovers new functions of the mSWI/SNF during human corticogenesis, identifying cell-autonomous defects in axonogenesis as a cause of ACC in ARID1B patients. O_FIG O_LINKSMALLFIG WIDTH=193 HEIGHT=200 SRC="FIGDIR/small/539362v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@dd4e9aorg.highwire.dtl.DTLVardef@153a081org.highwire.dtl.DTLVardef@14e884corg.highwire.dtl.DTLVardef@d64081_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstractC_FLOATNO Human callosal projection neurons are vulnerable to ARID1B haploinsufficiency. (Top) During healthy development, callosal projection neurons (CPNs) project long interhemispheric axons, forming the corpus callosum (CC) tract, which can be modeled in vitro. (Bottom) In ARID1B patients, transcriptional dysregulation of genetic programs of CC development reduces the formation of long-range projections from CPNs, causing CC agenesis in vivo and underconnectivity phenotypes in vitro. C_FIG

neuroscience↗

bioRxiv2022

Morphogenesis and development of human telencephalic organoids in the absence and presence of exogenous ECM

Establishment and maintenance of apical-basal polarity is a fundamental step in brain development, instructing the organization of neural progenitor cells (NPCs) and the developing cerebral cortex. Particularly, basally located extracellular matrix (ECM) is crucial for this process. In vitro, epithelial polarization can be achieved via endogenous ECM production, or exogenous ECM supplementation. While neuroepithelial development is recapitulated in cerebral organoids, the effects of different ECM sources in tissue morphogenesis remain unexplored. Here, we show that exposure to exogenous ECM at early neuroepithelial stages causes rapid tissue polarization and complete rearrangement of neuroepithelial architecture within 3 days. In unexposed cultures, endogenous ECM production by NPCs results in gradual polarity acquisition over an extended time. After the onset of neurogenesis, tissue architecture and neuronal differentiation are largely independent of the initial ECM source. These results advance the knowledge on neuroepithelial biology in vitro, with a focus on mechanisms of exogenously- and endogenously-guided morphogenesis. They demonstrate the self-sustainability of neuroepithelial cultures by endogenous processes, prompting an urgent reassessment of indiscriminate use of exogenous ECM in these model systems.

developmental biology↗

bioRxiv2022

Single-cell brain organoid screening identifies developmental defects in autism

Development of the human brain involves processes that are not seen in many other species, but can contribute to neurodevelopmental disorders (1-4). Cerebral organoids can be used to investigate neurodevelopmental disorders in a human context but are limited by variability and low throughput. We have developed the CRISPR-human organoids-scRNA-seq (CHOOSE) system that utilizes verified pairs of gRNAs, inducible CRISPR/Cas9-based genetic disruption, and single-cell transcriptomics for pooled loss-of-function screening in mosaic organoids. Genetic perturbations of 36 high-risk autism spectrum disorder (ASD) genes related to transcriptional regulation allowed us to identify their effects on cell fate determination and discover developmental stages susceptible to ASD gene perturbations. We construct a developmental gene regulatory network (GRN) of cerebral organoids from single-cell multiomic data including transcriptome and chromatin modalities and identify ASD-associated and perturbation-enriched regulatory modules. We show that perturbing members of the BAF chromatin remodeling complex leads to an expanded population of ventral telencephalon progenitors. Specifically, the BAF subunit ARID1B controls the fate transitions of progenitors to oligodendrocyte precursor cells and interneurons, which we confirmed in patient-specific induced pluripotent stem cell (iPSC) derived organoids. Our study paves the way for phenotypically characterizing disease susceptibility genes in human organoid models with cell type, developmental trajectory, and gene regulatory network readouts.

developmental biology↗