Minor spliceosome inactivation causes microcephaly, owing to cell cycle defects and death of self-amplifying radial glial cells
Related Experiment Video
Updated: Feb 6, 2026
Assessing Cell Viability and Death in 3D Spheroid Cultures of Cancer Cells
Published on: June 16, 2019
Marybeth Baumgartner1,2, Anouk M Olthof1, Gabriela S Aquino1
1Physiology and Neurobiology Department, University of Connecticut, Storrs, CT 06269, USA.
Abstract:
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 Rnu11, which encodes the crucial minor spliceosome small nuclear RNA (snRNA) U11. Rnu11 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.
Insights
Disrupting the minor spliceosome, essential for cell development, caused microcephaly in mice by triggering radial glial cell death. This highlights the minor spliceosome's critical role in preventing developmental disorders like MOPD1.
Area of Science:
- Developmental Biology
- Molecular Genetics
- Cell Biology
Background:
- Mutations in minor spliceosome components are associated with microcephalic osteodysplastic primordial dwarfism type 1 (MOPD1).
- The minor spliceosome's role in mammalian development is not fully understood.
Purpose of the Study:
- To investigate the function of the minor spliceosome in mammalian brain development.
- To elucidate the cellular mechanisms underlying microcephaly in MOPD1.
Main Methods:
- Conditional knockout of Rnu11, encoding U11 snRNA, in developing mouse cortex.
- RNA sequencing to analyze gene expression changes in Rnu11-deficient cells.
- Analysis of cell cycle progression and DNA damage in radial glial cells.
Main Results:
- Rnu11 ablation led to microcephaly in mice due to radial glial cell death.
- U11-deficient radial glial cells showed p53 upregulation and DNA damage.
- Loss of minor splicing resulted in increased minor intron retention in cell cycle genes, affecting RGC proliferation.
Conclusions:
- Self-amplifying radial glial cells are highly sensitive to minor splicing defects.
- Disruption of minor splicing can cause microcephaly through radial glial cell apoptosis and cell cycle dysregulation.
- These findings offer a potential mechanism for microcephaly in MOPD1.
Related Concept Videos
01:04Glial Cells
01:58X-Inactivation
01:18Autophagic Cell Death
Autophagy and Apoptosis
Autophagy can activate apoptosis. In normal conditions, the autophagy activating protein Beclin-1 and...
01:30Overview of Cell Death
Cell death was observed in the early 19th century, but there was no experimental evidence to prove it. In 1842, Carl Vogt first discovered cell death in a metamorphic toad; however, it was not termed ‘cell death.’ Scientists discovered different cell death pathways only in the...
00:56What is the Cell Cycle?
01:04What is the Cell Cycle?