Minor spliceosome inactivation causes microcephaly, owing 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 D.; Sturrock, Nikita; Nguyen, Nhut; Seesi, Sahar Al; Kanadia, Rahul N.

doi:10.1242/dev.166322

Cited by 48 publications

(135 citation statements)

References 58 publications

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“…5a, 5c). The increase in mitotic cells in the E11.5 mutant forelimb and E12.5 mutant hindlimb could be caused by a delay in progenitor cell progression through the mitotic phases, as we previously found in the U11-null pallium 9 . Therefore, we performed IF for AuroraB, as its subcellular localization can be used to identify prophase, prometaphase, metaphase, anaphase, and telophase (Fig.…”

Section: Resultssupporting

confidence: 71%

“…2i, 3c-d). Defective cell cycle progression and subsequently reduced cell cycle speed led us to hypothesize that rapidly dividing cells would undergo apoptosis, as we have previously observed 9 .…”

Section: Resultsmentioning

confidence: 86%

“…Since minor intron retention can introduce a premature stop codon and result in nuclear degradation or nonsense mediated decay (NMD), we analyzed the effect of minor intron retention on the open reading frame (ORF) of these 152 MIGs 3,9 . Indeed, we found that minor intron retention almost invariably resulted in the introduction of a premature stop codon (150/152; 98.6%) (Supp.…”

Section: Resultsmentioning

confidence: 99%

“…2c; Supp. Data File 1) 3,9 . Some of these MIGs are crucial for cell cycle regulation, including Cdc45 , Mau2 , and Spc24 , which suggested that the limb defects observed in our mutant mice stem from cell cycle dysregulation (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Here we leverage our Rnu11 Flx/Flx mouse to inhibit the minor spliceosome in the developing limb by using Prrx1 -Cre, which is expressed at embryonic day (E) 9.5 in the forelimb and E10.5 in the hindlimb 9,20 . We show that limb size is reduced upon minor spliceosome inhibition, such that the severity corresponded to the developmental time at which U11 was lost.…”

Section: Introductionmentioning

confidence: 99%

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Minor spliceosome disruption causes limb growth defects without altering patterning

Lemoine

et al. 2020

Preprint

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Disruption of the minor spliceosome causes primordial dwarfism in microcephalic osteodysplastic primordial dwarfism type 1. Similarly, primordial dwarfism in domesticated animals is linked to positive selection in minor spliceosome components. Despite the importance of minor intron splicing in limb size regulation, its role in limb development remains unexplored. Here we show that loss of U11 small nuclear RNA, an essential minor spliceosome component, results in stunted limbs that maintain patterning. 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. Limb progenitor cells experience delayed prometaphase to metaphase transition and prolonged S-phase, resulting in death of rapidly dividing, distally located progenitors. Consequently, crucial limb patterning genes are upregulated and their expression is maintained spatially to achieve basic patterning. Overall, these findings reveal a potential mechanism shared in disease and domestication.The minor spliceosome, which consists of five small nuclear RNAs (snRNAs) U11, U12, U4atac, U5, and U6atac and associated proteins, splices <0.5% of introns, termed minor introns, found in <2% of genes, termed minor intron-containing genes (MIGs) 1-3 . In metazoans, the minor spliceosome, MIGs, and the position of minor introns within MIGs are all highly conserved 4-6 . This conservation could be explained by the enrichment of MIGs in essential functions required for cell survival 7 , which is consistent with embryonic lethality observed in multiple animal models with constitutive loss of minor spliceosome function [8][9][10] . Consequently, it is unsurprising that human diseases with minor spliceosome loss-of-function mutations have not been discovered. However, mutations that result in partial loss of minor spliceosome function have been reported [11][12][13][14][15][16] .For example, microcephalic osteodysplastic primordial dwarfism type 1 (MOPD1), Roifman syndrome (RS), and Lowry-Wood syndrome (LWS) are linked to partial inhibition of the minor spliceosome 11,12,14,16 . Here, individuals harbor disparate mutations in RNU4ATAC, which encodes the U4atac snRNA, and display symptoms including microcephaly, micrognathia, vertebral deficits, and primordial dwarfism 16,17 . The severity of primordial dwarfism observed in MOPD1, RS, and LWS is observed along a gradation, with MOPD1 being the most severe, RS moderate, and LWS mild 16,17 . Nonetheless, in all cases, the basic patterning of the limb skeletal elements, including the presence of a stylopod (humerus; femur), zeugopod (radius/ulna; tibia/fibula), and autopod (hand; foot), is maintained 16,17 .Since unique mutations in RNU4ATAC have been linked to MOPD1, RS, and LWS, the gradation of primordial dwarfism might be due to differential inhibition of the minor spliceosome 16,17 . This suggests that the activity of the minor spliceosome might serve as a rheostat for tissue size cont...

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Section: Resultssupporting

confidence: 71%

Section: Resultsmentioning

confidence: 86%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Minor spliceosome disruption causes limb growth defects without altering patterning

Lemoine

et al. 2020

Preprint

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Posttranscriptional Control of Brain Development

Musso,

Lupan,

Silver

2023

Neocortical Neurogenesis in Development and Evolution

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An apparent new syndrome of extreme short stature, microcephaly, dysmorphic faces, intellectual disability, and a bone dysplasia of unknown etiology

Stinson

Brault

Delk

et al. 2020

American J of Med Genetics Pt A

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We report on a 26-year-old male with extreme short stature, microcephaly, macroglossia, other dysmorphic features, severe intellectual disability, and a bone dysplasia. The patient had an extensive genetic and biochemical evaluation that was all normal or noninformative. Recently, the proband died following a period of not eating. He likely had a previously undescribed syndrome of unknown etiology.

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

Cited by 48 publications

References 58 publications

Minor spliceosome disruption causes limb growth defects without altering patterning

Minor spliceosome disruption causes limb growth defects without altering patterning

Posttranscriptional Control of Brain Development

An apparent new syndrome of extreme short stature, microcephaly, dysmorphic faces, intellectual disability, and a bone dysplasia of unknown etiology

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