Lalli, E. | Search bioRxiv

bioRxiv2025

Hippo/YAP1 Signaling Regulates the Oligodendrocyte-Astrocyte Fate Switch and Ependymal Gene Expression in Adult Spinal Cord Stem Cells

The adult mammalian spinal cord harbors ependymal cells that retain neural stem-cell properties. Although they possess a latent capacity to generate oligodendrocytes, these cells predominantly differentiate into astrocytes after injury. The molecular cues that govern their lineage commitment toward astrocytic versus oligodendroglial fates remain poorly defined. In this study, we addressed this gap in vitro by investigating the emergence of PDGFRA oligodendrocyte precursor cells (OPCs) in neurosphere cultures derived from adult spinal cord stem cells. We first observed that neurosphere cells exhibited a hybrid identity, co-expressing transcription factors of both astrocytic (NFIA, SOX9) and oligodendrocytic (OLIG1/2, SOX4, NKX2.2, TCF4) lineages. Upon differentiation, oligodendrocytic transcription factors were selectively maintained in OPCs but reduced in other cells. Using PdgfraH2B-GFP mice, we then isolated newly formed PDGFRA OPCs from neurospheres and performed multi-omic profiling. OPC formation was associated with the upregulation of chromatin remodelers and the downregulation of stem-cell markers such as EGFR, HES1, and TNC. Strikingly, OPC specification coincided with reduced expression of YAP1 and its partner TEAD1, key effectors of the Hippo pathway. Functional analyses revealed that YAP1 loss enhanced oligodendrocytic differentiation while reducing astrocytic and ependymal/cilia-associated gene expression. Conversely, constitutive YAP1 activation blocked differentiation into both lineages and promoted an ependymal-like transcriptional program, including upregulation of the ependymal marker CD24a and cilia-related proteins such as CROCC (Rootletin). Collectively, these findings uncover previously unrecognized roles for YAP1 in adult spinal cord stem-cell fate decisions and provide a molecular framework for leveraging these cells in regenerative strategies targeting spinal cord repair.

cell biology↗

bioRxiv2023

Defects in AMPAR trafficking and microglia activation underlie socio-cognitive deficits associated to decreased expression of Phosphodiesterase 2A

Phosphodiesterase 2A (PDE2A) is an enzyme involved in the homeostasis of cAMP and cGMP and is the most highly expressed PDE in human brain regions critical for socio-cognitive behavior. In cortex and hippocampus, PDE2A expression level is upregulated in Fmr1-KO mice, a model of the Fragile X Syndrome (FXS), the most common form of inherited intellectual disability (ID) and autism spectrum disorder (ASD). Indeed, PDE2A translation is negatively modulated by FMRP, whose functional absence causes FXS. While the pharmacological inhibition of PDE2A has been associated to its pro-cognitive role in normal animals and in models of ID and ASD, homozygous PDE2A mutations have been identified in patients affected by ID, ASD and epilepsy. To clarify this apparent paradox about the role of PDE2A in brain development, we characterized here Pde2a+/- mice (homozygote animals being not viable) at the behavioral, cellular, molecular and electrophysiological levels. Pde2a+/- females display a milder form of the disorder with reduced cognitive performance in adulthood, conversely males show severe socio-cognitive deficits throughout their life. In males, these phenotypes are associated with microglia activation, elevated glutathione levels and increased externalization of GluR1 in CA1, producing reduced mGluR-dependent LTD. Overall, our results reveal molecular targets of the PDE2A-dependent pathway underlying socio-cognitive performance. These results clarify the mechanism of action of pro-cognitive drugs based on PDE2A inactivation, which have been shown to be promising therapeutic approaches for Alzheimer Disease, schizophrenia, FXS as well as other forms of ASD.

animal behavior and cognition↗