Biology subjects

Troglio, F.

Publications and source records attributed to Troglio, F..

4 recordsLinked to original sources

bioRxiv2022

GTF2I dosage regulates neuronal differentiation and social behavior in 7q11.23 neurodevelopmental disorders

Copy number variations at 7q11.23 cause neurodevelopmental disorders with shared and opposite manifestations. Deletion causes Williams-Beuren syndrome (WBS), while duplication causes 7q11.23 microduplication syndrome (7Dup). Converging evidence indicates GTF2I, from the 7q11.23 locus, is a key mediator of the cognitive-behavioral phenotypes associated with WBS and 7Dup. Here we integrate molecular profiling of patient-derived cortical organoids (COs) and transgenic mouse models to dissect 7q11.23 disease mechanisms. Proteomic and transcriptomic profiling of COs revealed opposite dynamics of neural progenitor proliferation and transcriptional imbalances, leading to precocious excitatory neuron production in 7Dup. The accelerated excitatory neuron production in 7Dup COs could be rescued by GTF2I knockdown. Transgenic mice with Gtf2i duplication recapitulated early neuronal differentiation defects and ASD-like behaviors. Remarkably, inhibition of LSD1, a downstream effector of GTF2I, was sufficient to rescue ASD-like phenotypes. We propose that the GTF2I-LSD1 axis constitutes a molecular pathway amenable to therapeutic intervention.

neuroscience↗

bioRxiv2022

7q11.23 CNV alters protein synthesis and REST-mediated neuronal intrinsic excitability

Copy number variations (CNVs) at 7q11.23 cause Williams-Beuren (WBS) and 7q microduplication syndromes (7Dup), two neurodevelopmental disorders with shared and opposite cognitive-behavioral phenotypes. Using patient-derived and isogenic neurons, we integrated transcriptomics, translatomics and proteomics to elucidate the molecular underpinnings of this dosage effect. We found that 7q11.23 CNVs cause opposite alterations in neuronal differentiation and excitability. Genes related to neuronal transmission chiefly followed 7q11.23 dosage and appeared transcriptionally controlled, while translation and ribosomal protein genes followed the opposite trend and were post-transcriptionally buffered. Mechanistically, we uncovered REST regulon as a key mediator of observed phenotypes and rescued transcriptional and excitability alterations through REST inhibition. We identified downregulation of global protein synthesis, mGLUR5 and ERK-mTOR pathways activity in steady-state in both WBS and 7Dup, whereas BDNF stimulation rescued them specifically in 7Dup. Overall, we show that 7q11.23 CNVs alter protein synthesis and neuronal firing-established molecular and cellular phenotypes of neurodevelopmental disorders. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/511483v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@1b0fa99org.highwire.dtl.DTLVardef@146624org.highwire.dtl.DTLVardef@13dc89aorg.highwire.dtl.DTLVardef@13d098f_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2022

Benchmarking brain organoid recapitulation of fetal corticogenesis

Brain organoids are becoming increasingly relevant to dissect the molecular mechanisms underlying psychiatric and neurological conditions. The in vitro recapitulation of key features of human brain development affords the unique opportunity of investigating the developmental antecedents of neuropsychiatric conditions in the context of the actual patients genetic backgrounds. Specifically, multiple strategies of brain organoid (BO) differentiation have enabled the investigation of human cerebral corticogenesis in vitro with increasing accuracy. However, the field lacks a systematic investigation of how closely the gene co-expression patterns seen in cultured BO from different protocols match those observed in fetal cortex, a paramount information for ensuring the sensitivity and accuracy of modeling disease trajectories. Here we benchmark BO against fetal corticogenesis by integrating transcriptomes from in-house differentiated cortical BO (CBO), other BO systems, human fetal brain samples processed in-house, and prenatal cortices from the BrainSpan Atlas. We identified co-expression patterns and prioritized hubs of human corticogenesis and CBO differentiation, highlighting both well-preserved and discordant trends across BO protocols, including different degrees of heterochronicity in differentiation across BO models compared to fetal cortex. Our approach provides a framework to directly compare the extent of in vivo/in vitro alignment of neurodevelopmentally relevant processes and their attending temporalities, structured as an accessible resource to query for modelling human corticogenesis and the neuropsychiatric outcomes of its alterations.

developmental biology↗

bioRxiv2018

Longitudinal dissection in brain organoids at single cell resolution uncovers the developmental role of GSK3 in human corticogenesis

The regulation of proliferation and polarity of neural progenitors is crucial for the development of the brain cortex, with modes and timings of cell division intimately related to the stereotypical acquisition of layer-specific neuronal identities. Animal studies have implicated glycogen synthase kinase 3 (GSK3) as a pivotal regulator of both proliferation and polarity, yet the functional relevance of its signaling for the unique features of human corticogenesis remain to be elucidated. Here we harness human cortical brain organoids to probe, at single cell resolution, the longitudinal impact of GSK3 inhibition through multiple developmental stages. Our results indicate that chronic GSK3 inhibition increases the proliferation of neural progenitors and causes massive derangement of cortical tissue architecture. Surprisingly, single cell transcriptome profiling revealed only a discrete impact on early neurogenesis and uncovered the outer radial glia and the astrogenic lineage as the main GSK3-dependent developmental domains. Through this first single cell-level dissection of the GSK3 regulatory network in human corticogenesis, our work uncovers a remarkably specific conduit between the architecture of progenitor niches and lineage specification.

developmental biology↗