Minor spliceosome inactivation in the developing mouse cortex causes self-amplifying radial glial cell death and microcephaly

Abstract

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 StatementHere we report the first mammalian model to investigate the role of the minor spliceosome in cortical development and microcephaly.List of abbreviations usedMOPD1=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

Functional Interplay between Small Non-Coding RNAs and RNA Modification in the Brain

“…The microcephaly observed in children with MOPD-I implies that neuronal precursors are among the cell types most affected by the loss of this snRNA. Neuronal precursor loss resulting in microcephaly is also observed after deletion of the minor spliceosomal snRNA U11 in the developing mouse cortex [ 155 ], and inactivation of U12 in the postnatal mouse retina results in apoptosis of differentiating retinal cells [ 156 ]. The observation that all four snRNAs unique to the minor spliceosome are enriched in the developing mouse brain [ 156 ] further underscores their importance in neurodevelopment.…”