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Emerging evidence links oligodendrocyte (OL) lineage cells and myelin to cognitive processes, yet the role of myelination in shaping neuronal networks critical for cognitive tasks remains unknown. We demonstrate in mice that early postnatal GABAergic signaling between interneurons and oligodendrocyte precursor cells (OPCs) is crucial for myelination of parvalbumin (PV) interneurons, which facilitates in vivo low-gamma oscillations in the medial prefrontal cortex (mPFC) and supports fear extinction learning. Disruption of this signaling results in PV interneuron dysmyelination, decreases low-gamma power, and impairs tone fear extinction. These deficits are specific to PV interneuron dysmyelination, as mPFC myelination, high-gamma oscillations and contextual fear extinction are not significantly altered. Increasing PV interneuron activity or enhancing myelination do not reverse the deficits, indicating the long-term consequences of these early myelination impairments. Our findings reveal the role of OPC GABAergic signaling in PV interneuron myelination and mPFC circuit maturation, with lasting impacts on gamma rhythms and cognition. Early postnatal interneuron-oligodendroglia communication may shape neuronal networks underlying cognition. Here, the authors show that disrupting this signaling in mice impairs interneuron myelination, gamma rhythms, and fear-related learning.

ANKRD11 (Ankyrin Repeat Domain 11) is a chromatin regulator and a causative gene for KBG syndrome, a rare developmental disorder characterized by multiple organ abnormalities, including cardiac defects. However, the role of ANKRD11 in heart development is unknown. The neural crest plays a leading role in embryonic heart development, and its dysfunction is implicated in congenital heart defects. We demonstrate that conditional knockout of Ankrd11 in the murine embryonic neural crest results in persistent truncus arteriosus, ventricular dilation, and impaired ventricular contractility. We further show these defects occur due to aberrant cardiac neural crest cell organization leading to outflow tract septation failure. Lastly, knockout of Ankrd11 in the neural crest leads to impaired expression of various transcription factors, chromatin remodelers and signaling pathways, including mTOR, BMP and TGF-β in the cardiac neural crest cells. In this work, we identify Ankrd11 as a regulator of neural crest-mediated heart development and function. Ankrd11 is a chromatin regulator that is strongly associated with KBG syndrome, a rare disorder that includes heart defects. Here they show that loss of Ankrd11 from neural crest dysregulates cardiac neural crest cell organization and crucial signaling pathways, leading to failed heart outflow tract septation and severe cardiac defects.

ANKRD11 (ankyrin repeat domain 11) is a chromatin regulator and the only gene associated with KBG syndrome, a rare neurodevelopmental disorder. We have previously shown that Ankrd11 regulates murine embryonic cortical neurogenesis. Here, we show a novel olfactory bulb phenotype in a KBG syndrome mouse model and two diagnosed patients. Conditional knockout of Ankrd11 in murine embryonic neural stem cells leads to aberrant postnatal olfactory bulb development and reduced size due to reduction of the olfactory bulb granule cell layer. We further show that the rostral migratory stream has incomplete migration of neuroblasts, reduced cell proliferation as well as aberrant differentiation of neurons. This leads to reduced neuroblasts and neurons in the olfactory bulb granule cell layer. In vitro, Ankrd11 -deficient neural stem cells from the postnatal subventricular zone display reduced migration, proliferation, and neurogenesis. Finally, we describe two clinically and molecularly confirmed KBG syndrome patients with anosmia and olfactory bulb and groove hypo-dysgenesis/agenesis. Our report provides evidence that Ankrd11 is a novel regulator of olfactory bulb development and neuroblast migration. Moreover, our study highlights a novel clinical sign of KBG syndrome linked to ANKRD11 perturbations in mice and humans.

The mammalian adult brain contains two neural stem and precursor (NPC) niches: the subventricular zone [SVZ] lining the lateral ventricles and the subgranular zone [SGZ] in the hippocampus. From these, SVZ NPCs represent the largest NPC pool. While SGZ NPCs typically only produce neurons and astrocytes, SVZ NPCs produce neurons, astrocytes and oligodendrocytes throughout life. Of particular importance is the generation and replacement of oligodendrocytes, the only myelinating cells of the central nervous system (CNS). SVZ NPCs contribute to myelination by regenerating the parenchymal oligodendrocyte precursor cell (OPC) pool and by differentiating into oligodendrocytes in the developing and demyelinated brain. The neurosphere assay has been widely adopted by the scientific community to facilitate the study of NPCs in vitro . Here, we present a streamlined protocol for culturing postnatal and adult SVZ NPCs and OPCs from primary neurosphere cells. We characterize the purity and differentiation potential as well as provide RNA-sequencing profiles of postnatal SVZ NPCs, postnatal SVZ OPCs and adult SVZ NPCs. We show that primary neurospheres cells generated from postnatal and adult SVZ differentiate into neurons, astrocytes and oligodendrocytes concurrently and at comparable levels. SVZ OPCs are generated by subjecting primary neurosphere cells to OPC growth factors fibroblast growth factor (FGF) and platelet-derived growth factor-AA (PDGF-AA). We further show SVZ OPCs can differentiate into oligodendrocytes in the absence and presence of thyroid hormone T3. Transcriptomic analysis confirmed the identities of each cell population and revealed novel immune and signalling pathways expressed in an age and cell type specific manner. Graphical Abstract

Emerging evidence links oligodendrocyte (OL) lineage cells and myelin to cognitive processes, yet the role of myelination in shaping neuronal networks critical for cognitive tasks remains unknown. We demonstrate that early postnatal GABAergic signaling between interneurons and oligodendrocyte precursor cells (OPCs) is crucial for myelination of parvalbumin (PV) interneurons, which facilitates in vivo low-gamma oscillations in the medial prefrontal cortex (mPFC) and supports fear extinction learning. Disruption of this signaling resulted in PV interneuron dysmyelination, decreased low-gamma power, and impaired tone fear extinction. These deficits were specific to PV interneuron dysmyelination, as overall mPFC myelination, high-gamma oscillations and context fear extinction remained unaffected. Increasing PV interneuron activity or enhancing myelination did not reverse the deficits, indicating the long-term consequences of these early myelination impairments. Our findings reveal critical roles of OPC GABAergic signaling in PV interneuron myelination and mPFC circuit maturation, with lasting impacts on gamma rhythms and cognitive function.Competing Interest StatementThe authors have declared no competing interest.Footnotes* https://gitlab.com/d5674/c_ibaceta/psd-volt

CD33 is an immunomodulatory receptor expressed on microglia and genetically linked to Alzheimer’s disease (AD) susceptibility. While antibodies targeting CD33 have entered clinical trials to treat neurodegeneration, it is unknown whether the glycan-binding properties of CD33 can be exploited to modulate microglia. Here, we use liposomes that multivalently display glycan ligands of CD33 (CD33L liposomes) to engage CD33. We find that CD33L liposomes increase phagocytosis of cultured monocytic cells and microglia in a CD33-dependent manner. Enhanced phagocytosis strongly correlates with loss of CD33 from the cell surface and internalization of liposomes. Increased phagocytosis by treatment with CD33L liposomes is dependent on a key intracellular signaling motif on CD33 as well as the glycan-binding ability of CD33. These effects are specific to trans engagement of CD33 by CD33L liposomes, as cis engagement through insertion of lipid-linked CD33L into cells produces the opposite effect on phagocytosis. Moreover, intracerebroventricular injection of CD33L liposomes in mice enhances phagocytosis of microglia in a CD33-dependent manner. These results demonstrate that multivalent engagement of CD33 with glycan ligands can modulate microglial cell function.

Epigenetic and chromatin regulation of craniofacial development remains poorly understood. Ankyrin Repeat Domain 11 ( ANKRD11 ) is a chromatin regulator that has previously been shown to control neural stem cell fates via modulation of histone acetylation. ANKRD11 gene variants, or microdeletions of the 16q24.3 chromosomal region encompassing the ANKRD11 gene, cause KBG syndrome, a rare autosomal dominant congenital disorder with variable neurodevelopmental and craniofacial involvement. Craniofacial abnormalities include a distinct facial gestalt, delayed bone age, tooth abnormalities, delayed fontanelle closure, and frequently cleft or submucosal palate. Despite this, the dramatic phenotype and precise role of ANKRD11 in embryonic craniofacial development remain unexplored. Quantitative analysis of 3D images of KBG syndromic subjects shows an overall reduction in the size of the middle and lower face. Here, we report that mice with heterozygous deletion of Ankrd11 in neural crest cells (Ankrd11 nchet ) display a mild midfacial hypoplasia including reduced midfacial width and a persistent open fontanelle, both of which mirror KBG syndrome patient facial phenotypes. Mice with a homozygous Ankrd11 deletion in neural crest cells (Ankrd11 ncko ) die at birth. They show increased severity of several clinical manifestations described for KBG syndrome, such as cleft palate, retrognathia, midfacial hypoplasia, and reduced calvarial growth. At E14.5, Ankrd11 expression in the craniofacial complex is closely associated with developing bony structures, while expression at birth is markedly decreased. Conditional deletion of Ankrd11 leads to a reduction in ossification of midfacial bones, with several ossification centers failing to expand and/or fuse. Intramembranous bones show features of delayed maturation, with bone remodeling severely curtailed at birth. Palatal shelves remain hypoplastic at all developmental stages, with a local reduction in proliferation at E13.5. Our study identifies Ankrd11 as a critical regulator of intramembranous ossification and palate development and suggests that Ankrd11 nchet and Ankrd11 ncko mice may serve as pre-clinical models for KBG syndrome in humans.