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Loss of U11 small nuclear RNA in the developing mouse limb results in micromelia
Kyle D Drake1, Christopher Lemoine1,2, Gabriela S Aquino1
1Physiology and Neurobiology Department, University of Connecticut, Storrs, CT 06269, USA.
Abstract:
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 owing 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.
Insights
Disrupting the minor spliceosome, essential for cell cycle regulation, causes limb growth defects. This finding reveals a shared mechanism in primordial dwarfism and animal domestication.
Area of Science:
- Molecular Biology
- Developmental Biology
- Genetics
Background:
- Mutations in RNU4ATAC disrupt the minor spliceosome, causing primordial dwarfism syndromes like Roifman syndrome.
- Positive selection in minor spliceosome components is linked to dwarfism in domesticated animals.
- The minor spliceosome's role in limb development and size regulation is largely unknown.
Purpose of the Study:
- To investigate the function of the minor spliceosome in mammalian limb development.
- To determine the molecular mechanisms underlying minor spliceosome-mediated size control.
Main Methods:
- Ablation of U11 small nuclear RNA in developing mouse limbs to disrupt minor spliceosome function.
- Analysis of limb size, cell cycle progression, and gene expression in affected limbs.
Main Results:
- U11 ablation led to micromelia (reduced limb size).
- Loss of U11 caused increased minor intron retention in cell cycle genes, leading to cell cycle delays (prometaphase-to-metaphase transition, S-phase).
- Rapidly dividing progenitor cell death and limb size reduction occurred, yet limb patterning gene expression remained intact.
Conclusions:
- The minor spliceosome is essential for normal limb development and size regulation in mice.
- Minor intron retention and subsequent cell cycle defects in progenitor cells are key mechanisms for size control.
- The findings suggest a conserved role for the minor spliceosome in size regulation relevant to both human diseases and animal domestication.
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