title: Muscleblind-like 2-mediated alternative splicing in the developing brain and dysregulation in myotonic dystrophy.
abstract: The RNA-mediated disease model for myotonic dystrophy (DM) proposes that microsatellite C(C)TG expansions express toxic RNAs that disrupt splicing regulation by altering MBNL1 and CELF1 activities. While this model explains DM manifestations in muscle, less is known about the effects of C(C)UG expression on the brain. Here, we report that Mbnl2 knockout mice develop several DM-associated central nervous system (CNS) features including abnormal REM sleep propensity and deficits in spatial memory. Mbnl2 is prominently expressed in the hippocampus and Mbnl2 knockouts show a decrease in NMDA receptor (NMDAR) synaptic transmission and impaired hippocampal synaptic plasticity. While Mbnl2 loss did not significantly alter target transcript levels in the hippocampus, misregulated splicing of hundreds of exons was detected using splicing microarrays, RNA-seq, and HITS-CLIP. Importantly, the majority of the Mbnl2-regulated exons examined were similarly misregulated in DM. We propose that major pathological features of the DM brain result from disruption of the MBNL2-mediated developmental splicing program.
authors.affiliation: Department of Molecular Genetics and Microbiology and the Center for NeuroGenetics, University of Florida, College of Medicine, Gainesville, FL 32610, USA.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Charizanis
authors.forename: Kuang-Yung
authors.initials: KY
authors.lastname: Lee
authors.forename: Ranjan
authors.initials: R
authors.lastname: Batra
authors.forename: Marianne
authors.initials: M
authors.lastname: Goodwin
authors.forename: Chaolin
authors.initials: C
authors.lastname: Zhang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yuan
authors.forename: Lily
authors.initials: L
authors.lastname: Shiue
authors.forename: Melissa
authors.initials: M
authors.lastname: Cline
authors.forename: Marina M
authors.initials: MM
authors.lastname: Scotti
authors.forename: Guangbin
authors.initials: G
authors.lastname: Xia
authors.forename: Ashok
authors.initials: A
authors.lastname: Kumar
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Ashizawa
authors.forename: H Brent
authors.initials: HB
authors.lastname: Clark
authors.forename: Takashi
authors.initials: T
authors.lastname: Kimura
authors.forename: Masanori P
authors.initials: MP
authors.lastname: Takahashi
authors.forename: Harutoshi
authors.initials: H
authors.lastname: Fujimura
authors.forename: Kenji
authors.initials: K
authors.lastname: Jinnai
authors.forename: Hiroo
authors.initials: H
authors.lastname: Yoshikawa
authors.forename: Mário
authors.initials: M
authors.lastname: Gomes-Pereira
authors.forename: Geneviève
authors.initials: G
authors.lastname: Gourdon
authors.forename: Noriaki
authors.initials: N
authors.lastname: Sakai
authors.forename: Seiji
authors.initials: S
authors.lastname: Nishino
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Foster
authors.forename: Manuel
authors.initials: M
authors.lastname: Ares
authors.forename: Robert B
authors.initials: RB
authors.lastname: Darnell
authors.forename: Maurice S
authors.initials: MS
authors.lastname: Swanson
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000503:physiopathology*; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009223:Myotonic Dystrophy / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D009473:Neuronal Plasticity / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D009435:Synaptic Transmission / Q000235:genetics
chemical_list: C529512:Mbnl2 protein, mouse; D016601:RNA-Binding Proteins