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Precocious neuronal differentiation and disrupted oxygen responses in Kabuki syndrome
Giovanni A. Carosso, … , Loyal A. Goff, Hans T. Bjornsson
Giovanni A. Carosso, … , Loyal A. Goff, Hans T. Bjornsson
Published August 29, 2019
Citation Information: JCI Insight. 2019;4(20):e129375. https://doi.org/10.1172/jci.insight.129375.
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Research Article Genetics Neuroscience

Precocious neuronal differentiation and disrupted oxygen responses in Kabuki syndrome

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Abstract

Chromatin modifiers act to coordinate gene expression changes critical to neuronal differentiation from neural stem/progenitor cells (NSPCs). Lysine-specific methyltransferase 2D (KMT2D) encodes a histone methyltransferase that promotes transcriptional activation and is frequently mutated in cancers and in the majority (>70%) of patients diagnosed with the congenital, multisystem intellectual disability disorder Kabuki syndrome 1 (KS1). Critical roles for KMT2D are established in various non-neural tissues, but the effects of KMT2D loss in brain cell development have not been described. We conducted parallel studies of proliferation, differentiation, transcription, and chromatin profiling in KMT2D-deficient human and mouse models to define KMT2D-regulated functions in neurodevelopmental contexts, including adult-born hippocampal NSPCs in vivo and in vitro. We report cell-autonomous defects in proliferation, cell cycle, and survival, accompanied by early NSPC maturation in several KMT2D-deficient model systems. Transcriptional suppression in KMT2D-deficient cells indicated strong perturbation of hypoxia-responsive metabolism pathways. Functional experiments confirmed abnormalities of cellular hypoxia responses in KMT2D-deficient neural cells and accelerated NSPC maturation in vivo. Together, our findings support a model in which loss of KMT2D function suppresses expression of oxygen-responsive gene programs important to neural progenitor maintenance, resulting in precocious neuronal differentiation in a mouse model of KS1.

Authors

Giovanni A. Carosso, Leandros Boukas, Jonathan J. Augustin, Ha Nam Nguyen, Briana L. Winer, Gabrielle H. Cannon, Johanna D. Robertson, Li Zhang, Kasper D. Hansen, Loyal A. Goff, Hans T. Bjornsson

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Figure 5

In vivo defects of neurogenesis and NSPC differentiation in a Kmt2d+/βgeo mouse model of KS1.

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In vivo defects of neurogenesis and NSPC differentiation in a Kmt2d+/βge...
(A) Immunostaining images of dividing (EdU-pulsed) dentate gyrus (DG) NSPCs and nuclei purified from microdissected DG by fluorescence-activated cell sorting (FACS) (B) of labeled nuclei. (C) Cell cycle analysis in purified EdU+ DG nuclei from Kmt2d+/+ and Kmt2d+/βgeo mice sampled 16 hours after pulse, using DAPI fluorescence (13–14 mice per genotype, 200–500 nuclei per mouse). (D) Representative confocal immunostaining of neurogenesis markers in the DG of adult Kmt2d+/+ and Kmt2d+/βgeo mice at steady state (6–10 mice per genotype, 7–10 Z-stack images per mouse) or after EdU pulse (5–6 mice per genotype, 10 Z-stack images per mouse). NES+ radial glia-like (RGL) NSPCs, in either quiescent (minichromosome maintenance complex component 2–negative, MCM2–) or activated (MCM2+) states (qRGL and aRGL, respectively), MCM2+ NES946 intermediate progenitor cells (IPCs), and DCX+ neuroblasts (NBs) were quantified. (E and F) Quantification of stage-specific NSPC densities (qRGL, aRGL, IPC, and NB) in adult Kmt2d+/+ and Kmt2dβ/geo mice at steady state (E) or after EdU pulse-chase (2 weeks) to birth date, differentiating NSPCs (F). Bars indicate mean ± SEM. One-tailed Student’s t test (*P < 0.05, **P < 0.01, and ***P < 0.001). Scale bars: 50 μm, unless otherwise specified (A, inset, 10 μm).

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