Neurodevelopmental deficits and cell-type-specific transcriptomic perturbations in a mouse model of HNRNPU haploinsufficiency.

Autor: Dugger SA; Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, New York, United States of America.; Department of Genetics and Development, Columbia University Irving Medical Center, New York, New York, United States of America., Dhindsa RS; Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, New York, United States of America.; Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, United States of America.; Jan and Dan Duncan Neurological Research Institute of Texas Children's Hospital, Houston, Texas, United States of America., Sampaio GA; Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, New York, United States of America., Ressler AK; Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, New York, United States of America., Rafikian EE; Mouse Neurobehavioral Core Facility, Columbia University Irving Medical Center, New York, New York, United States of America., Petri S; Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, New York, United States of America., Letts VA; Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, New York, United States of America., Teoh J; Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, New York, United States of America., Ye J; Department of Biochemistry and Molecular Biophysics, Columbia University Irving Medical Center, New York, New York, United States of America.; Zuckerman Mind Brain and Behavior Institute, Columbia University, New York, New York, United States of America., Colombo S; Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, New York, United States of America., Peng Y; Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, New York, United States of America.; Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York, United States of America., Yang M; Mouse Neurobehavioral Core Facility, Columbia University Irving Medical Center, New York, New York, United States of America., Boland MJ; Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, New York, United States of America.; Department of Neurology, Columbia University Irving Medical Center, New York, New York, United States of America., Frankel WN; Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, New York, United States of America.; Department of Genetics and Development, Columbia University Irving Medical Center, New York, New York, United States of America., Goldstein DB; Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, New York, United States of America.; Department of Genetics and Development, Columbia University Irving Medical Center, New York, New York, United States of America.
Jazyk: angličtina
Zdroj: PLoS genetics [PLoS Genet] 2023 Oct 02; Vol. 19 (10), pp. e1010952. Date of Electronic Publication: 2023 Oct 02 (Print Publication: 2023).
DOI: 10.1371/journal.pgen.1010952
Abstrakt: Heterozygous de novo loss-of-function mutations in the gene expression regulator HNRNPU cause an early-onset developmental and epileptic encephalopathy. To gain insight into pathological mechanisms and lay the potential groundwork for developing targeted therapies, we characterized the neurophysiologic and cell-type-specific transcriptomic consequences of a mouse model of HNRNPU haploinsufficiency. Heterozygous mutants demonstrated global developmental delay, impaired ultrasonic vocalizations, cognitive dysfunction and increased seizure susceptibility, thus modeling aspects of the human disease. Single-cell RNA-sequencing of hippocampal and neocortical cells revealed widespread, yet modest, dysregulation of gene expression across mutant neuronal subtypes. We observed an increased burden of differentially-expressed genes in mutant excitatory neurons of the subiculum-a region of the hippocampus implicated in temporal lobe epilepsy. Evaluation of transcriptomic signature reversal as a therapeutic strategy highlights the potential importance of generating cell-type-specific signatures. Overall, this work provides insight into HNRNPU-mediated disease mechanisms and provides a framework for using single-cell RNA-sequencing to study transcriptional regulators implicated in disease.
Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests. D.B.G. is a founder of Actio Biosciences, a founder of and holds equity in Praxis, serves as a consultant to AstraZeneca, and has received research support from Janssen, Gilead, Biogen, AstraZeneca and UCB. R.S.D serves as a consultant to AstraZeneca. S.C. serves a consultant for Q-State Biosciences, Inc.
(Copyright: © 2023 Dugger et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Databáze: MEDLINE
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