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Minor spliceosome inactivation causes microcephaly, owing to cell cycle defects and death of self-amplifying radial glial cells.
Development. 2018 08 28; 145(17)D

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.

Authors+Show Affiliations

Physiology and Neurobiology Department, University of Connecticut, Storrs, CT 06269, USA. Connecticut Institute for the Brain and Cognitive Sciences, University of Connecticut, Storrs, CT 06269, USA.Physiology and Neurobiology Department, University of Connecticut, Storrs, CT 06269, USA.Physiology and Neurobiology Department, University of Connecticut, Storrs, CT 06269, USA.Physiology and Neurobiology Department, University of Connecticut, Storrs, CT 06269, USA.Physiology and Neurobiology Department, University of Connecticut, Storrs, CT 06269, USA. College of Medicine, University of Illinois, Chicago, IL 60612, USA.Physiology and Neurobiology Department, University of Connecticut, Storrs, CT 06269, USA.Physiology and Neurobiology Department, University of Connecticut, Storrs, CT 06269, USA. Biological and Biomedical Sciences Program, Harvard Medical School, Boston, MA 02115, USA.Physiology and Neurobiology Department, University of Connecticut, Storrs, CT 06269, USA.Computer Science Engineering Department, University of Connecticut, Storrs, CT 06269, USA.Physiology and Neurobiology Department, University of Connecticut, Storrs, CT 06269, USA rahul.kanadia@uconn.edu. Institute of Systems Genomics, University of Connecticut, Storrs, CT 06269, USA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30093551

Citation

Baumgartner, Marybeth, et al. "Minor Spliceosome Inactivation Causes Microcephaly, Owing to Cell Cycle Defects and Death of Self-amplifying Radial Glial Cells." Development (Cambridge, England), vol. 145, no. 17, 2018.
Baumgartner M, Olthof AM, Aquino GS, et al. Minor spliceosome inactivation causes microcephaly, owing to cell cycle defects and death of self-amplifying radial glial cells. Development. 2018;145(17).
Baumgartner, M., Olthof, A. M., Aquino, G. S., Hyatt, K. C., Lemoine, C., Drake, K., Sturrock, N., Nguyen, N., Al Seesi, S., & Kanadia, R. N. (2018). Minor spliceosome inactivation causes microcephaly, owing to cell cycle defects and death of self-amplifying radial glial cells. Development (Cambridge, England), 145(17). https://doi.org/10.1242/dev.166322
Baumgartner M, et al. Minor Spliceosome Inactivation Causes Microcephaly, Owing to Cell Cycle Defects and Death of Self-amplifying Radial Glial Cells. Development. 2018 08 28;145(17) PubMed PMID: 30093551.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Minor spliceosome inactivation causes microcephaly, owing to cell cycle defects and death of self-amplifying radial glial cells. AU - Baumgartner,Marybeth, AU - Olthof,Anouk M, AU - Aquino,Gabriela S, AU - Hyatt,Katery C, AU - Lemoine,Christopher, AU - Drake,Kyle, AU - Sturrock,Nikita, AU - Nguyen,Nhut, AU - Al Seesi,Sahar, AU - Kanadia,Rahul N, Y1 - 2018/08/28/ PY - 2018/05/01/received PY - 2018/07/13/accepted PY - 2018/8/11/pubmed PY - 2018/10/16/medline PY - 2018/8/11/entrez KW - Cell cycle KW - Cortical development KW - Microcephaly KW - Minor spliceosome KW - Radial glial cells KW - U11 snRNA JF - Development (Cambridge, England) JO - Development VL - 145 IS - 17 N2 - 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. SN - 1477-9129 UR - https://www.unboundmedicine.com/medline/citation/30093551/Minor_spliceosome_inactivation_causes_microcephaly_owing_to_cell_cycle_defects_and_death_of_self_amplifying_radial_glial_cells_ L2 - http://dev.biologists.org/cgi/pmidlookup?view=long&pmid=30093551 DB - PRIME DP - Unbound Medicine ER -