Biology subjects

del Toro, D.

Publications and source records attributed to del Toro, D..

4 recordsLinked to original sources

bioRxiv2024

A double hit affecting the IKZF1-IKZF2 tandem in immune cells of schizophrenic patients regulate specific symptoms

Schizophrenia is a complex multifactorial disorder and increasing evidence suggests the involvement of immune dysregulations in its pathogenesis. We observed that IKZF1 and IKZF2, classic immune-related transcription factors (TFs), were both downregulated in patients peripheral blood mononuclear cells (PBMCs) but not in their brain. We generated a new mutant mouse model with a reduction in Ikzf1 and Ikzf2 to study the impact of those changes. Such mice developed deficits in the three dimensions (positive-negative-cognitive) of schizophrenic-like phenotypes associated with alterations in structural synaptic plasticity. We then studied the secretomes of cultured PBMCs obtained from human patients and identified potentially secreted molecules, which depended on IKZF1 and IKZF2 levels, and that in turn have an impact on neural synchrony, structural synaptic plasticity and schizophrenic-like symptoms in in vivo and in vitro models. Our results point out that IKZF1-IKZF2-dependent immune signals negatively impact on essential neural circuits involved in schizophrenia.

neuroscience↗

bioRxiv2024

Cortex Folding by Combined Progenitor Expansion and Adhesion-Controlled Neuronal Migration

Folding of the mammalian cerebral cortex into sulcal fissures and gyral peaks is the result of complex processes that are incompletely understood. Previously we showed that genetic deletion of Flrt1/3 adhesion molecules causes folding of the smooth mouse cortex into sulci resulting from increased lateral dispersion and faster neuron migration, without progenitor expansion. Here, we find that combining the Flrt1/3 double knockout with an additional genetic deletion that causes progenitor expansion, greatly enhances cortex folding. Expansion of intermediate progenitors by deletion of Cep83 results in enhanced formation of sulci. Expansion of apical progenitors by deletion of Fgf10 results in enhanced formation of gyri. Single cell transcriptomics and simulations suggest that changes in adhesive properties of cortical neurons, their proportions and densities in the cortical plate, combined with lateral dispersion during their radial migration are important folding parameters. These results identify key developmental mechanisms that cooperate to promote cortical gyrification. HIGHLIGHTSO_LICortex folding is enhanced by combining progenitor expansion and divergent migration. C_LIO_LIConcomitant expansion of intermediate progenitors results in the formation of sulci C_LIO_LIConcomitant expansion of apical progenitors results in the formation of gyri C_LIO_LIProgenitors differentially affect cortical neurons with distinct adhesive properties C_LI

neuroscience↗

bioRxiv2023

Expansion of the neocortex and protection from neurodegeneration by in vivo transient reprogramming

Yamanaka factors (YFs) can reverse some aging features in mammalian tissues, but their effects on the brain remain largely unexplored. Here, we induced YFs in the mouse brain in a controlled spatio-temporal manner in two different scenarios: brain development, and adult stages in the context of neurodegeneration. Embryonic induction of YFs perturbed cell identity of both progenitors and neurons, but transient and low-level expression is tolerated by these cells during development. Under these conditions, YFs induction led to expanded neurogenesis, increased number of upper cortical neurons, and enhanced motor and social behavior of adult mice. Additionally, controlled YF induction is tolerated by principal neurons in the adult dorsal hippocampus and prevented the development of several hallmarks of Alzheimers disease, including cognitive decline and altered molecular signatures, in the 5xFAD mouse model. Overall, these results highlight the powerful impact of YFs on neurogenesis and their potential use in brain disorders. HighlightsO_LITransient Yamanaka factor (YF) expression during development expands neocortex C_LIO_LIYF-treated mice show enhanced cognitive skills C_LIO_LIIntermitent YF expression is tolerated by adult principal hippocampal neurons C_LIO_LILong-term intermitent YF reprogramming is protective in an AD mouse model C_LI

neuroscience↗

bioRxiv2022

GPC3-Unc5D complex structure and role in cell migration

Neural migration is a critical step during brain development that requires the interactions of cell-surface guidance receptors. Cancer cells often hijack these mechanisms to disseminate. Here we reveal crystal structures of Uncoordinated-5 receptor D (Unc5D) in complex with morphogen receptor glypican-3 (GPC3), forming an octameric glycoprotein complex. In the complex, four Unc5D molecules pack into an antiparallel bundle, flanked by four GPC3 molecules. Central glycan-glycan interactions are formed by N-linked glycans emanating from GPC3 (N241 in human) and C-mannosylated tryptophans of the Unc5D thrombospondin-like domains. MD simulations, mass-spectrometry and structure-based mutants validate the crystallographic data. Anti-GPC3 nanobodies enhance or weaken Unc5-GPC3 binding. Using these tools in vivo, we show that Unc5/GPC3 guide migrating pyramidal neurons in the mouse cortex, and cancer cells in an embryonic xenograft neuroblastoma model. The results demonstrate a conserved structural mechanism of cell-guidance, with the potential for wide- ranging biomedical implications in development and cancer biology.

neuroscience↗