Dataset Information

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.

SUBMITTER: Drake KD

PROVIDER: S-EPMC7438004 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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

Drake Kyle D KD Lemoine Christopher C Aquino Gabriela S GS Vaeth Anna M AM Kanadia Rahul N RN

Development (Cambridge, England) 20200814 21

Disruption of the minor spliceosome due to mutations in <i>RNU4ATAC</i> 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 abla ...[more]

PMID: 32665241

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Project description:Fetal alcohol spectrum disorders (FASD) are heterogeneous disorders associated with alcohol exposure to the developing fetus that are characterized by a range of adverse neurodevelopmental deficits. Despite the numerous genomics and genetic studies on FASD models, the comprehensive molecular understanding of the mechanisms that underlie FASD-related neurodevelopmental deficits remains elusive. Circular RNAs (circRNAs) are a subtype of long non-coding RNAs that are derived from back-splicing and covalent joining of exons and/or introns of protein-coding genes. Recent studies have shown that circRNAs are highly enriched in the brain, where they are developmentally regulated. However, the role of the majority of brain-enriched circRNAs in normal and pathological brain development and function has not been explored yet. Here we carried out the first systematic profiling of circRNA expression in response to prenatal alcohol exposure (PAE) in male and female embryonic day 18 (E18) whole brains. We observed that the changes in circRNA expression in response to PAE were notably sex-specific and that PAE tended to erase most of the sex-specificity in circRNA expression present in control (saccharin-treated) mice. On the other hand, RNA sequencing (RNA-seq) in the same samples showed that changes in protein-coding gene expression were not predominantly sex-specific. Using circRNA quantitative real-time PCR (qRT-PCR), we validated that circSatb2, which is generated from the special AT-rich sequence-binding protein 2 (Satb2) gene, is significantly upregulated in the brain of E18 male PAE mice. We also show that circPtchd2, a circRNA synthesized from dispatched RND transporter family member 3 (Disp3, also known as Ptchd2), exhibits significantly higher expression in E18 control but not PAE female mouse brain relative to males. Taken together, our results demonstrate that PAE differentially alters circRNA expression in the developing brain in a sex-specific manner.

Dataset Information

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

Publications

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

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