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

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.

doi:10.1242/dev.166322

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RESEARCH ARTICLE| 01 January 2018

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

In collection: Neural development , Stem cells & regeneration

Marybeth Baumgartner,

Marybeth Baumgartner #

1

Physiology and Neurobiology Department, University of Connecticut, Storrs, CT 06269, USA

2

Connecticut Institute for the Brain and Cognitive Sciences, University of Connecticut, Storrs, CT 06269, USA

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Anouk M. Olthof,

Anouk M. Olthof #

1

Physiology and Neurobiology Department, University of Connecticut, Storrs, CT 06269, USA

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Gabriela S. Aquino,

Gabriela S. Aquino

1

Physiology and Neurobiology Department, University of Connecticut, Storrs, CT 06269, USA

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Katery C. Hyatt,

Katery C. Hyatt

1

Physiology and Neurobiology Department, University of Connecticut, Storrs, CT 06269, USA

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Christopher Lemoine,

Christopher Lemoine

1

Physiology and Neurobiology Department, University of Connecticut, Storrs, CT 06269, USA

3

College of Medicine, University of Illinois, Chicago, IL 60612, USA

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Kyle Drake,

Kyle Drake

1

Physiology and Neurobiology Department, University of Connecticut, Storrs, CT 06269, USA

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Nikita Sturrock,

Nikita Sturrock

1

Physiology and Neurobiology Department, University of Connecticut, Storrs, CT 06269, USA

4

Harvard Medical School, Boston, MA 02115, USA

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Nhut Nguyen,

Nhut Nguyen

1

Physiology and Neurobiology Department, University of Connecticut, Storrs, CT 06269, USA

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Sahar al Seesi,

Sahar al Seesi

5

Computer Science Engineering Department, University of Connecticut, Storrs, CT 06269, USA

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Rahul N. Kanadia

0000-0001-7197-912X

Rahul N. Kanadia *

1

Physiology and Neurobiology Department, University of Connecticut, Storrs, CT 06269, USA

6

Institute of Systems Genomics, University of Connecticut, Storrs, CT 06269, USA

*Author for correspondence: rahul.kanadia@uconn.edu

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Author and article information

Marybeth Baumgartner #

1

Physiology and Neurobiology Department, University of Connecticut, Storrs, CT 06269, USA

2

Connecticut Institute for the Brain and Cognitive Sciences, University of Connecticut, Storrs, CT 06269, USA

Anouk M. Olthof #

1

Physiology and Neurobiology Department, University of Connecticut, Storrs, CT 06269, USA

Gabriela S. Aquino

1

Physiology and Neurobiology Department, University of Connecticut, Storrs, CT 06269, USA

Katery C. Hyatt

1

Physiology and Neurobiology Department, University of Connecticut, Storrs, CT 06269, USA

Christopher Lemoine

1

Physiology and Neurobiology Department, University of Connecticut, Storrs, CT 06269, USA

3

College of Medicine, University of Illinois, Chicago, IL 60612, USA

Kyle Drake

1

Physiology and Neurobiology Department, University of Connecticut, Storrs, CT 06269, USA

Nikita Sturrock

1

Physiology and Neurobiology Department, University of Connecticut, Storrs, CT 06269, USA

4

Harvard Medical School, Boston, MA 02115, USA

Nhut Nguyen

1

Physiology and Neurobiology Department, University of Connecticut, Storrs, CT 06269, USA

Sahar al Seesi

5

Computer Science Engineering Department, University of Connecticut, Storrs, CT 06269, USA

Rahul N. Kanadia

https://orcid.org/0000-0001-7197-912X

*

1

Physiology and Neurobiology Department, University of Connecticut, Storrs, CT 06269, USA

6

Institute of Systems Genomics, University of Connecticut, Storrs, CT 06269, USA

*Author for correspondence: rahul.kanadia@uconn.edu

#

Contributed equally

Received: 01 May 2018

Accepted: 13 Jul 2018

Online ISSN: 1477-9129

Print ISSN: 0950-1991

Funding

National Institute of Neurological Disorders and Stroke (1R21NS096684-01A1)

2018

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Development dev.166322.

https://doi.org/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 Rnu11, which encodes the crucial minor spliceosome 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. RNAseq suggested that this cell death was mediated by upregulation of p53 and DNA damage, which were both observed specifically in U11-null RGCs. Moreover, U11 loss caused elevated minor intron retention in genes regulating 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.

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2018

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