BubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice

Darren J. Baker; Karthik B. Jeganathan; J. Douglas Cameron; Michael Thompson; Subhash Juneja; Alena Kopecka; Rajiv Kumar; Robert B. Jenkins; Piet C. De Groen; Patrick Roche; Jan M. Van Deursen

doi:10.1038/ng1382

BubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice

Darren J. Baker, Karthik B. Jeganathan, J. Douglas Cameron, Michael Thompson, Subhash Juneja, Alena Kopecka, Rajiv Kumar, Robert B. Jenkins, Piet C. De Groen, Patrick Roche, Jan M. Van Deursen

Medicine - Gastro, Hepatology, Nutrition Division

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634 Scopus citations

Abstract

Faithful segregation of replicated chromosomes is essential for maintenance of genetic stability and seems to be monitored by several mitotic checkpoints. Various components of these checkpoints have been identified in mammals, but their physiological relevance is largely unknown. Here we show that mutant mice with low levels of the spindle assembly checkpoint protein BubR1 develop progressive aneuploidy along with a variety of progeroid features, including short lifespan, cachectic dwarfism, lordokyphosis, cataracts, loss of subcutaneous fat and impaired wound healing. Graded reduction of BubR1 expression in mouse embryonic fibroblasts causes increased aneuploidy and senescence. Male and female mutant mice have defects in meiotic chromosome segregation and are infertile. Natural aging of wild-type mice is marked by decreased expression of BubR1 in multiple tissues, including testis and ovary. These results suggest a role for BubR1 in regulating aging and infertility.

Original language	English (US)
Pages (from-to)	744-749
Number of pages	6
Journal	Nature Genetics
Volume	36
Issue number	7
DOIs	https://doi.org/10.1038/ng1382
State	Published - Jul 2004

Bibliographical note

Funding Information:
We thank J. Harden, R. Babu, M. Gazi, S. Guyse, M. Pittelkow, R. Goorha, J. Davenport, D. Pearson, K. Hafner (Cytogenetics Shared Resource), J. van Ree and S. Kaufman for supporting this project; R. Bram for critically reviewing the manuscript and for discussions; and T. Yen for providing BubR1 antibody. This work was supported by a grant from the US National Institutes of Health.

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title = "BubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice",

abstract = "Faithful segregation of replicated chromosomes is essential for maintenance of genetic stability and seems to be monitored by several mitotic checkpoints. Various components of these checkpoints have been identified in mammals, but their physiological relevance is largely unknown. Here we show that mutant mice with low levels of the spindle assembly checkpoint protein BubR1 develop progressive aneuploidy along with a variety of progeroid features, including short lifespan, cachectic dwarfism, lordokyphosis, cataracts, loss of subcutaneous fat and impaired wound healing. Graded reduction of BubR1 expression in mouse embryonic fibroblasts causes increased aneuploidy and senescence. Male and female mutant mice have defects in meiotic chromosome segregation and are infertile. Natural aging of wild-type mice is marked by decreased expression of BubR1 in multiple tissues, including testis and ovary. These results suggest a role for BubR1 in regulating aging and infertility.",

author = "Baker, {Darren J.} and Jeganathan, {Karthik B.} and Cameron, {J. Douglas} and Michael Thompson and Subhash Juneja and Alena Kopecka and Rajiv Kumar and Jenkins, {Robert B.} and {De Groen}, {Piet C.} and Patrick Roche and {Van Deursen}, {Jan M.}",

note = "Funding Information: We thank J. Harden, R. Babu, M. Gazi, S. Guyse, M. Pittelkow, R. Goorha, J. Davenport, D. Pearson, K. Hafner (Cytogenetics Shared Resource), J. van Ree and S. Kaufman for supporting this project; R. Bram for critically reviewing the manuscript and for discussions; and T. Yen for providing BubR1 antibody. This work was supported by a grant from the US National Institutes of Health.",

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AU - Baker, Darren J.

AU - Jeganathan, Karthik B.

AU - Cameron, J. Douglas

AU - Thompson, Michael

AU - Juneja, Subhash

AU - Kopecka, Alena

AU - Kumar, Rajiv

AU - Jenkins, Robert B.

AU - De Groen, Piet C.

AU - Roche, Patrick

AU - Van Deursen, Jan M.

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PY - 2004/7

Y1 - 2004/7

N2 - Faithful segregation of replicated chromosomes is essential for maintenance of genetic stability and seems to be monitored by several mitotic checkpoints. Various components of these checkpoints have been identified in mammals, but their physiological relevance is largely unknown. Here we show that mutant mice with low levels of the spindle assembly checkpoint protein BubR1 develop progressive aneuploidy along with a variety of progeroid features, including short lifespan, cachectic dwarfism, lordokyphosis, cataracts, loss of subcutaneous fat and impaired wound healing. Graded reduction of BubR1 expression in mouse embryonic fibroblasts causes increased aneuploidy and senescence. Male and female mutant mice have defects in meiotic chromosome segregation and are infertile. Natural aging of wild-type mice is marked by decreased expression of BubR1 in multiple tissues, including testis and ovary. These results suggest a role for BubR1 in regulating aging and infertility.

AB - Faithful segregation of replicated chromosomes is essential for maintenance of genetic stability and seems to be monitored by several mitotic checkpoints. Various components of these checkpoints have been identified in mammals, but their physiological relevance is largely unknown. Here we show that mutant mice with low levels of the spindle assembly checkpoint protein BubR1 develop progressive aneuploidy along with a variety of progeroid features, including short lifespan, cachectic dwarfism, lordokyphosis, cataracts, loss of subcutaneous fat and impaired wound healing. Graded reduction of BubR1 expression in mouse embryonic fibroblasts causes increased aneuploidy and senescence. Male and female mutant mice have defects in meiotic chromosome segregation and are infertile. Natural aging of wild-type mice is marked by decreased expression of BubR1 in multiple tissues, including testis and ovary. These results suggest a role for BubR1 in regulating aging and infertility.

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BubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice

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