Minor spliceosome inactivation causes microcephaly, owing to cell cycle defects and death of self-amplifying radial glial cells

• Published in: Development (Cambridge) Vol. 145; no. 17
• Main Authors: Baumgartner, Marybeth, Olthof, Anouk M, Aquino, Gabriela S, Hyatt, Katery C, Lemoine, Christopher, Drake, Kyle, Sturrock, Nikita, Nguyen, Nhut, Al Seesi, Sahar, Kanadia, Rahul N
• Format: Journal Article
• Language: English
• Published: England The Company of Biologists Ltd 28-08-2018
• Subjects: Animals; Base Sequence; Cell Cycle - genetics; Cell Death - physiology; Dwarfism - genetics; Ependymoglial Cells - metabolism; Fetal Growth Retardation - genetics; Mice; Mice, Inbred C57BL; Mice, Knockout; Microcephaly - genetics; Neural Stem Cells - cytology; Osteochondrodysplasias - genetics; RNA Splicing - genetics; RNA, Small Nuclear - genetics; Spliceosomes - genetics; Spliceosomes - metabolism; Stem Cells and Regeneration; Tumor Suppressor Protein p53 - biosynthesis; Radial glial cells; Cortical development; U11 snRNA; Minor spliceosome; Microcephaly; Cell cycle
• ISSN: 0950-1991; 1477-9129
• DOI: 10.1242/dev.166322

Mutation in minor spliceosome components is linked to the developmental disorder microcephalic osteodysplastic primordial dwarfism type 1 (MOPD1). Here, we inactivated the minor spliceosome in the developing mouse cortex (pallium) by ablating
, which encodes the crucial minor spliceosome small nuclear RNA (snRNA) U11.
conditional knockout mice were born with microcephaly, which was caused by the death of self-amplifying radial glial cells (RGCs), while intermediate progenitor cells and neurons were produced. RNA sequencing suggested that this cell death was mediated by upregulation of p53 (Trp53 - Mouse Genome Informatics) and DNA damage, which were both observed specifically in U11-null RGCs. Moreover, U11 loss caused elevated minor intron retention in genes regulating the cell cycle, which was consistent with fewer RGCs in S-phase and cytokinesis, alongside prolonged metaphase in RGCs. In all, we found that self-amplifying RGCs are the cell type most sensitive to loss of minor splicing. Together, these findings provide a potential explanation of how disruption of minor splicing might cause microcephaly in MOPD1.