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

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.

Integrity of the minor spliceosome in the developing mouse hypothalamus determines neuronal subtype composition regulating energy balance

“…Here, we show that integrity of the minor spliceosome is essential for hypothalamic development and function. Specifically, we show that ablation of Rnu11 inhibits the minor spliceosome, which resulted in elevated minor intron retention and aberrant AS of MIGs involved in cell cycle regulation, consistent with previous reports 40,51,44,43 . As expected, we found progenitor cell cycle defect in the VD ( Fig.…”

Minor intron splicing efficiency increases with the development of lethal prostate cancer

“…In fact, siU6atac resulted in the largest number of MIGs with elevated minor intron retention compared to published reports of MiS inhibition with other components [44][45][46] . Unlike MiS inhibition through other components 13,37,45 , the largest AS events observed in siU6atac samples were cryptic splicing events executed by the major spliceosome (Fig. 3D).…”

Taxonomy of introns, their evolution, and the role of minor introns in stress response

“…While binary intron classification based on splice site sequence has proven useful for elucidating the mechanism of minor intron splicing, next generation sequencing of genomes and transcriptomes has revealed a wide diversity in consensus sequences. Moreover, several lines of research have reported that not all bioinformatically classified minor introns are affected upon minor spliceosome inhibition (10)(11)(12)(13)(14), suggesting that this dichotomous classification of introns is an oversimplification. Gaining insight into the targets of each spliceosome will enhance our ability to uncover the mechanism of disease pathogenesis of spliceosomopathies, a group of inherited disorders caused by mutations in spliceosome components (15).…”