Nearly complete deletion of BubR1 causes microcephaly through shortened mitosis and massive cell death

Ambrosia J. Simmons, Raehee Park, Noelle A. Sterling, Mi-Hyeon D Jang, Jan Van Deursen, Timothy J. Yen, Seo Hee Cho, Seonhee Kim

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1822-1836
Number of pages15
JournalHuman molecular genetics
Volume28
Issue number11
DOIs
StatePublished - Jun 1 2019
Externally publishedYes

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Microcephaly
M Phase Cell Cycle Checkpoints
Mitosis
Cell Death
Chromosome Segregation
Aneuploidy
Neurons
Congenital, Hereditary, and Neonatal Diseases and Abnormalities
Centrosome
Mutation
Cilia
Neurogenesis
Metaphase
Hydrocephalus
Chromosome Aberrations
Cerebral Cortex
benzimidazole
Proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Nearly complete deletion of BubR1 causes microcephaly through shortened mitosis and massive cell death. / Simmons, Ambrosia J.; Park, Raehee; Sterling, Noelle A.; Jang, Mi-Hyeon D; Van Deursen, Jan; Yen, Timothy J.; Cho, Seo Hee; Kim, Seonhee.

In: Human molecular genetics, Vol. 28, No. 11, 01.06.2019, p. 1822-1836.

Research output: Contribution to journalArticle

Simmons, Ambrosia J. ; Park, Raehee ; Sterling, Noelle A. ; Jang, Mi-Hyeon D ; Van Deursen, Jan ; Yen, Timothy J. ; Cho, Seo Hee ; Kim, Seonhee. / Nearly complete deletion of BubR1 causes microcephaly through shortened mitosis and massive cell death. In: Human molecular genetics. 2019 ; Vol. 28, No. 11. pp. 1822-1836.
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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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AU - Park, Raehee

AU - Sterling, Noelle A.

AU - Jang, Mi-Hyeon D

AU - Van Deursen, Jan

AU - Yen, Timothy J.

AU - Cho, Seo Hee

AU - Kim, Seonhee

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