Biology subjects

Parras, C.

Publications and source records attributed to Parras, C..

7 recordsLinked to original sources

bioRxiv2025

Post-translational Tuning of Human Cortical Progenitor Neuronal Output

The striking expansion of the human neocortex is driven by the ability of radial glial cells (RGCs) to prolong neurogenesis without exhausting their progenitor pool, thereby producing more neurons, particularly in the upper layers. The mechanisms underlying enhanced human neurogenic output remain unresolved. We hypothesized that post-translational modification of conserved proteins could provide a flexible mechanism supporting species-specific patterns of neurogenesis. Here, we identify phosphorylation of the proneural factor NEUROGENIN2 as a regulator of human RGC neuronal output by modulating its pioneering-like activity, at the expense of its transactivation function. This, in turn, remodels the RGC chromatin landscape, resulting in a forward temporal shift of RGC gene regulatory networks and leading to increased neuronal production biased towards upper-layer neurons. Our work proposes a conceptual framework for how subtle modifications of conserved processes, and not just new genes, encode tunable mechanisms for species-specific trajectories of brain development.

developmental biology↗

bioRxiv2024

Pharmacogenomic screening identifies and repurposes leucovorin and dyclonine as pro-oligodendrogenic compounds in brain repair

Oligodendrocytes are the myelin-forming cells of the central nervous system (CNS), with oligodendroglial pathologies leading to strong disabilities, from early preterm-birth brain injury (PBI) to adult multiple sclerosis (MS). No medication presenting convincing repair capacity in humans has been approved for these pathologies so far. Here, we present a pharmacogenomic approach leading to the identification of small bioactive molecules with a large pro-oligodendrogenic activity, selected through an expert curation scoring strategy (OligoScore) of their large impact on transcriptional programs controlling oligodendrogenesis and (re)myelination. We demonstrate the pro-oligodendrogenic activity of these compounds in vitro, using neural and oligodendrocyte progenitor cell (OPC) cultures, as well as ex vivo, using organotypic cerebellar explant cultures. Focusing on the two most promising molecules, i.e. leucovorin and dyclonine, we tested their therapeutic efficacy using a mouse model of neonatal chronic hypoxia, which faithfully mimics aspects of PBI. In this model, both compounds promoted proliferation and oligodendroglial fate acquisition from neural stem/progenitor cells, with leucovorin also promoting their differentiation. We extended these findings to an adult focal de/remyelination mouse MS model, in which both compounds improved lesion repair by promoting OPC differentiation while maintaining the pool of OPCs, and in parallel, by accelerating the transition from pro-inflammatory to pro-regenerative microglial profiles and myelin debris clearance. This study paves the way for clinical trials aimed at repurposing these FDA-approved compounds to treat myelin pathologies such as PBI and MS. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=139 SRC="FIGDIR/small/607135v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@83031eorg.highwire.dtl.DTLVardef@141d812org.highwire.dtl.DTLVardef@1d0a31corg.highwire.dtl.DTLVardef@848c67_HPS_FORMAT_FIGEXP M_FIG C_FIG Pharmacogenomic screening identifies and repurposes dyclonine and leucovorin as pro-oligodendrogenic and pro-myelinating compounds. Schematics of the pharmacogenomic approach leading to the identification of small bioactive molecules (compounds) with potential pro-oligodendrogenic activity, followed by the in vitro validation of the top compounds using neural and oligodendrocyte progenitor cell (OPC) cultures as well as organotypic cerebellar explants. The therapeutic efficacy of the top two compounds, leucovorin and dyclonine, both approved by the Food and Drug Administration (FDA), was assessed in vivo using two clinically relevant mouse models of myelin pathologies. In the neonatal hypoxia mouse model, mimicking some aspects of preterm brain injury, both leucovorin and dyclonine promoted neural stem cell (NSC) differentiation into OPCs and OPC proliferation, with leucovorin additionally restoring the density of myelinating OLs found in normoxic conditions. In an adult focal de/remyelination mouse model of multiple sclerosis, both compounds significantly improved lesion repair in adult mice by promoting OPC differentiation while preserving the pool of OPCs, and by accelerating myelin debris clearance and shifting microglia from pro-inflammatory to pro-regenerative profiles.

neuroscience↗

bioRxiv2022

Diversity within olfactory sensory derivatives revealed by the contribution of Dbx1 lineages

In vertebrates, the embryonic olfactory epithelium contains progenitors that will give rise to distinct classes of neurons, including olfactory sensory neurons (OSN, involved in odor detection), vomeronasal sensory neurons (VSN, responsible for pheromone sensing) and GnRH neurons that control the hypothalamic-pituitary-gonadal axis. Currently, these three neuronal lineages are usually believed to emerge from uniform pools of progenitors. Here we found that the homeodomain transcription factor Dbx1 is expressed by neurogenic progenitors in the developing and adult mouse olfactory epithelium. We demonstrate that Dbx1 itself is dispensable for neuronal fate specification and global organization of the olfactory sensory system. Using lineage tracing we characterize the contribution of Dbx1 lineages to OSN, VSN and GnRH neuron populations and reveal an unexpected degree of diversity. Furthermore, we demonstrate that Dbx1-expressing progenitors remain neurogenic in the absence of the proneural gene Ascl1. Our work therefore points to the existence of distinct neurogenic programs in Dbx1-derived and other olfactory lineages.

developmental biology↗

bioRxiv2022

Single cell analysis of the dorsal V-SVZ reveals differential quiescence of postnatal pallial and subpallial neural stem cells driven by TGFbeta/BMP-signalling

The ventricular-subventricular zone (V-SVZ) is the largest neurogenic region of the postnatal forebrain, containing neural stem cells (NSCs) that emerge from both the embryonic pallium and subpallium. Despite of this dual origin, glutamatergic neurogenesis declines rapidly after birth, while gabaergic neurogenesis persists throughout life. Here, we performed single-cell RNA-sequencing (scRNA-Seq) of the postnatal dorsal V-SVZ for unravelling the mechanisms leading to pallial lineage germinal activity silencing. We identify cell lineage-specific NSCs primed for the generation of neurons or glial cells, as well as a large population of so far uncharacterized quiescent NSCs (qNSC). Pallial qNSCs enter a state of deep quiescence, characterized by persistent TGFbeta/BMP signalling, reduced transcriptional activity and Hopx expression, whilst in contrast, subpallial qNSCs remain transcriptionally primed for activation. Induction of deep pallial quiescence is paralleled by a rapid blockade of glutamatergic neuron production and differentiation. Finally, manipulation of the TGFbeta/BMP receptor Bmpr1a demonstrate its key role in mediating these effects at early postnatal times. Together, our results highlight a central role of TGFbeta/BMP-signalling in synchronizing quiescence induction and blockade of neuronal differentiation to rapidly silence pallial germinal activity after birth.

neuroscience↗

bioRxiv2022

Transient regulation of focal adhesion via Tensin3 is required for nascent oligodendrocyte differentiation

The differentiation of oligodendroglia from oligodendrocyte precursor cells (OPCs) to complex and extensive myelinating oligodendrocytes (OLs) is a multistep process that involves largescale morphological changes with significant strain on the cytoskeleton. While key chromatin and transcriptional regulators of differentiation have been identified, their target genes responsible for the morphological changes occurring during OL myelination are still largely unknown. Here, we show that the regulator of focal adhesion, Tensin3 (Tns3), is a direct target gene of Olig2, Chd7, and Chd8, transcriptional regulators of OL differentiation. Tns3 is transiently upregulated and localized to cell processes of immature OLs, together with integrin-{beta}1, a key mediator of survival at this transient stage. Constitutive Tns3 loss-of-function leads to reduced viability in mouse and humans, with surviving knockout mice still expressing Tns3 in oligodendroglia. Acute deletion of Tns3 in vivo, either in postnatal neural stem cells (NSCs) or in OPCs, leads to a two-fold reduction in OL numbers. We find that the transient upregulation of Tns3 is required to protect differentiating OPCs and immature OLs from cell death by preventing the upregulation of p53, a key regulator of apoptosis. Altogether, our findings reveal a specific time window during which transcriptional upregulation of Tns3 in immature OLs is required for OL differentiation likely by mediating integrin-{beta}1 survival signaling to the actin cytoskeleton as OL undergo the large morphological changes required for their terminal differentiation.

neuroscience↗

bioRxiv2021

TCF12 controls oligodendroglial cell proliferation and regulates signaling pathways conserved in gliomas

Diffuse gliomas are primary brain tumors originating from the transformation of glial cells. In particular, oligodendrocyte precursor cells constitute the major tumor-amplifying population in the gliomagenic process. We previously identified the TCF12 gene, encoding a transcription factor of the E protein family, as being recurrently mutated in oligodendrogliomas. In this study, we sought to understand the function of TCF12 in oligodendroglial cells, the glioma lineage of origin. We first describe TCF12 mRNA and protein expression pattern in oligodendroglial development in the mouse brain. Second, by TCF12 genome wide chromatin profiling in oligodendroglial cells, we show that TCF12 binds active promoters of genes involved in proliferation, translation/ribosomes, and pathways involved in oligodendrocyte development and cancer. Finally, we perform OPC-specific Tcf12 inactivation in vivo and demonstrate by immunofluorescence and transcriptomic analyses that TCF12 is transiently required for OPC proliferation but dispensable for oligodendrocyte differentiation. We further show that Tcf12 inactivation results in deregulation of biological processes that are also altered in oligodendrogliomas. Together, our data suggest that TCF12 directly regulates transcriptional programs in oligodendroglia development that are relevant in a glioma context.

neuroscience↗

bioRxiv2021

The Amyloid Precursor Protein regulates human cortical neurogenesis

The approximately 16 billion neurons of the human neocortex are derived from a relatively limited number of developmental neural stem cells (NSCs). During embryogenesis, human cortical NSCs initially generate neurons at a particularly slow rate while preserving their progenitor state for a relatively long time. How this balance between the progenitor state and neurogenic state is regulated, and whether it contributes to species-specific brain patterning, is poorly understood. Here we show that the characteristic potential of human NSCs to remain in a progenitor state as they generate neurons for a prolonged amount of time requires the Amyloid Precursor Protein (APP). In contrast, APP is dispensable in mouse NSCs, which undergo neurogenesis at a much faster rate. Mechanistically, loss of APP cell-autonomously accelerates neurogenesis through activation of the AP1 transcription factor and repression of WNT signaling. We propose that the fine balance between self-renewal and differentiation is homeostatically regulated by APP, which may contribute to human-specific temporal patterns of neurogenesis.

developmental biology↗