ArticleHuman molecular genetics2019
Nearly complete deletion of BubR1 causes microcephaly through shortened mitosis and massive cell death.
Article in Human molecular genetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 27 citations in OpenAlex.
- Cdk7 promotes neuritogenesis in cortical neurons and contributes to social behavior in mice.Cellular and molecular life sciences : CMLS · 2026Article
- Evolutionary regulation of human Fas ligand (CD95L) by plasmin in solid cancer immunotherapy.Nature communications · 2025Article
- BubR1 Controls Heart Development by Promoting Expression of Cardiogenesis Regulators.Journal of the American Heart Association · 2025Article
- Mosaic variegated aneuploidy in development, ageing and cancer.Nature reviews. Genetics · 2024Review
- RNA sequencing and target long-read sequencing reveal an intronic transposon insertion causing aberrant splicing.Journal of human genetics · 2024Article
- Short-Term Effects of Human versus Bovine Sialylated Milk Oligosaccharide Microinjection on Zebrafish Larvae Survival, Locomotor Behavior and Gene Expression.International journal of molecular sciences · 2023Article
- P53 independent pathogenic mechanisms contribute to BubR1 microcephaly.Frontiers in cell and developmental biology · 2023Article
- Processing Neonatal Mouse Brains for Immunohistochemical Analysis: As Required for Including Spindle Orientation Analysis and Analysis of DNA Damage and Apoptosis.Methods in molecular biology (Clifton, N.J.) · 2023Article
- Clinical value and potential mechanisms of BUB1B up-regulation in nasopharyngeal carcinoma.BMC medical genomics · 2022Article
- Pathogenic correlation between mosaic variegated aneuploidy 1 (MVA1) and a novel BUB1B variant: a reappraisal of a severe syndrome.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2022Article
- Review
- Molecular contribution to embryonic aneuploidy and karyotypic complexity in initial cleavage divisions of mammalian development.Development (Cambridge, England) · 2022Article
- Research models of neurodevelopmental disorders: The right model in the right place.Frontiers in neuroscience · 2022Review
- Review
- Dissecting the Genetic and Etiological Causes of Primary Microcephaly.Frontiers in neurology · 2020Review
- Review
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
BUB-related 1 (BubR1) encoded by Budding Uninhibited by Benzimidazole 1B (BUB1B) is a crucial mitotic checkpoint protein ensuring proper segregation of chromosomes during mitosis. Mutations of BUB1B are responsible for mosaic variegated aneuploidy (MVA), a human congenital disorder characterized by extensive abnormalities in chromosome number. Although microcephaly is a prominent feature of MVA carrying the BUB1B mutation, how BubR1 deficiency disturbs neural progenitor proliferation and neuronal output and leads to microcephaly is unknown. Here we show that conditional loss of BubR1 in mouse cerebral cortex recapitulates microcephaly. BubR1-deficient cortex includes a strikingly reduced number of late-born, but not of early-born, neurons, although BubR1 expression is substantially reduced from an early stage. Importantly, absence of BubR1 decreases the proportion of neural progenitors in mitosis, specifically in metaphase, suggesting shortened mitosis owing to premature chromosome segregation. In the BubR1 mutant, massive apoptotic cell death, which is likely due to the compromised genomic integrity that results from aberrant mitosis, depletes progenitors and neurons during neurogenesis. There is no apparent alteration in centrosome number, spindle formation or primary cilia, suggesting that the major effect of BubR1 deficiency on neural progenitors is to impair the mitotic checkpoint. This finding highlights the importance of the mitotic checkpoint in the pathogenesis of microcephaly. Furthermore, the ependymal cell layer does not form in the conditional knockout, revealing an unrecognized role of BubR1 in assuring the integrity of the ventricular system, which may account for the presence of hydrocephalus in some patients.
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