Loss of U11 small nuclear RNA in the developing mouse limb results in micromelia

Drake, Kyle D.; Lemoine, Christopher; Aquino, Gabriela S.; Vaeth, Anna M.; Kanadia, Rahul N.

doi:10.1242/dev.190967

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RESEARCH ARTICLE| 01 January 2020

Loss of U11 small nuclear RNA in the developing mouse limb results in micromelia

Kyle D. Drake,

Kyle D. Drake

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

2

College of Medicine, University of Illinois, Chicago, IL 60612, 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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Anna M. Vaeth,

Anna M. Vaeth

1

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

3

Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, 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

4

Institute for System Genomics, University of Connecticut, Storrs, CT 06269, USA

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

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Author and article information

Kyle D. Drake

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

2

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

Gabriela S. Aquino

1

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

Anna M. Vaeth

1

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

3

Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA

Rahul N. Kanadia

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

*

1

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

4

Institute for System Genomics, University of Connecticut, Storrs, CT 06269, USA

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

Received: 27 Mar 2020

Accepted: 02 Jul 2020

Online ISSN: 1477-9129

Print ISSN: 0950-1991

Funding

National Science Foundation (IOS-1558046)

National Institutes of Health (F30 HL131298)

2020

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Development dev.190967.

https://doi.org/10.1242/dev.190967

Disruption of the minor spliceosome due to mutations in RNU4ATAC is linked to primordial dwarfism in microcephalic osteodysplastic primordial dwarfism type 1, Roifman syndrome, and Lowry-Wood syndrome. Similarly, primordial dwarfism in domesticated animals is linked to positive selection in minor spliceosome components. Despite being vital for limb development and size regulation, its role remains unexplored. Here we disrupt minor spliceosome function in the developing mouse limb by ablating one of its essential components, U11 small nuclear RNA, which resulted in micromelia. Notably, earlier loss of U11 corresponded to increased severity. We find that limb size is reduced due to elevated minor intron retention in minor intron-containing genes that regulate cell cycle. As a result, limb progenitor cells experience delayed prometaphase to metaphase transition and prolonged S-phase. Moreover, we observed death of rapidly dividing, distally located progenitors. Despite cell cycle defects and cell death, the spatial expression of key limb patterning genes was maintained. Overall, we show that the minor spliceosome is required for limb development via size control potentially shared in disease and domestication.

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2020

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