RT Journal Article
SR Electronic
T1 Minor spliceosome inactivation in the developing mouse cortex causes self-amplifying radial glial cell death and microcephaly
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 182816
DO 10.1101/182816
A1 Marybeth Baumgartner
A1 Anouk M. Olthof
A1 Katery C. Hyatt
A1 Christopher Lemoine
A1 Kyle Drake
A1 Nikita Sturrock
A1 Nhut Nguyen
A1 Sahar Al Seesi
A1 Rahul N. Kanadia
YR 2017
UL http://biorxiv.org/content/early/2017/08/31/182816.abstract
AB Inactivation of the minor spliceosome has been linked to microcephalic osteodysplastic primordial dwarfism type 1 (MOPD1). To interrogate how minor intron splicing regulates cortical development, we employed Emx1-Cre to ablate Rnu11, which encodes the minor spliceosome-specific U11 small nuclear RNA (snRNA), in the developing cortex (pallium). Rnu11 cKO mice were born with microcephaly, caused by death of self-amplifying radial glial cells (RGCs). However, both intermediate progenitor cells (IPCs) and neurons were produced in the U11-null pallium. RNAseq of the pallium revealed elevated minor intron retention in the mutant, particularly in genes regulating cell cycle. Moreover, the only downregulated minor intron-containing gene (MIG) was Spc24, which regulates kinetochore assembly. These findings were consistent with the observation of fewer RGCs entering cytokinesis prior to RGC loss, underscoring the requirement of minor splicing for cell cycle progression in RGCs. Overall, we provide a potential explanation of how disruption of minor splicing might cause microcephaly in MOPD1.Summary Statement Here we report the first mammalian model to investigate the role of the minor spliceosome in cortical development and microcephaly.List of abbreviations used MOPD1=microcephalic osteodysplastic primordial dwarfism type 1; snRNA=small nuclear RNA; cKO=conditional knockout; NPC=neural progenitor cell; RGC=radial glial cell; IPC=intermediate progenitor cell; MIG=minor intron-containing gene