The APC/C activator FZR1 is essential for meiotic prophase I in mice

Janet E. Holt, Victoria Pye, Evan Boon, Jessica L. Stewart, Irene García-Higuera, Sergio Moreno, Rubén Rodríguez, Keith T. Jones, Eileen A. McLaughlin

Research output: Contribution to journalArticle

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Abstract

Fizzy-related 1 (FZR1) is an activator of the Anaphase promoting complex/cyclosome (APC/C) and an important regulator of the mitotic cell division cycle. Using a germ-cell-specific conditional knockout model we examined its role in entry into meiosis and early meiotic events in both sexes. Loss of APC/CFZR1 activity in the male germline led to both a mitotic and a meiotic testicular defect resulting in infertility due to the absence of mature spermatozoa. Spermatogonia in the prepubertal testes of such mice had abnormal proliferation and delayed entry into meiosis. Although early recombination events were initiated, male germ cells failed to progress beyond zygotene and underwent apoptosis. Loss of APC/CFZR1 activity was associated with raised cyclin B1 levels, suggesting that CDK1 may trigger apoptosis. By contrast, female FZR1Δ mice were subfertile, with premature onset of ovarian failure by 5 months of age. Germ cell loss occurred embryonically in the ovary, around the time of the zygotenepachytene transition, similar to that observed in males. In addition, the transition of primordial follicles into the growing follicle pool in the neonatal ovary was abnormal, such that the primordial follicles were prematurely depleted. We conclude that APC/CFZR1 is an essential regulator of spermatogonial proliferation and early meiotic prophase I in both male and female germ cells and is therefore important in establishing the reproductive health of adult male and female mammals.

Original languageEnglish
Pages (from-to)1354-1365
Number of pages12
JournalDevelopment (Cambridge)
Volume141
Issue number6
DOIs
Publication statusPublished - 15 Mar 2014
Externally publishedYes

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Anaphase-Promoting Complex-Cyclosome
Meiotic Prophase I
Germ Cells
Meiosis
Ovary
Apoptosis
Cyclin B1
Spermatogonia
Reproductive Health
Infertility
Genetic Recombination
Spermatozoa
Testis
Mammals
Cell Cycle

Cite this

Holt, J. E., Pye, V., Boon, E., Stewart, J. L., García-Higuera, I., Moreno, S., ... McLaughlin, E. A. (2014). The APC/C activator FZR1 is essential for meiotic prophase I in mice. Development (Cambridge), 141(6), 1354-1365. https://doi.org/10.1242/dev.104828
Holt, Janet E. ; Pye, Victoria ; Boon, Evan ; Stewart, Jessica L. ; García-Higuera, Irene ; Moreno, Sergio ; Rodríguez, Rubén ; Jones, Keith T. ; McLaughlin, Eileen A. / The APC/C activator FZR1 is essential for meiotic prophase I in mice. In: Development (Cambridge). 2014 ; Vol. 141, No. 6. pp. 1354-1365.
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Holt, JE, Pye, V, Boon, E, Stewart, JL, García-Higuera, I, Moreno, S, Rodríguez, R, Jones, KT & McLaughlin, EA 2014, 'The APC/C activator FZR1 is essential for meiotic prophase I in mice', Development (Cambridge), vol. 141, no. 6, pp. 1354-1365. https://doi.org/10.1242/dev.104828

The APC/C activator FZR1 is essential for meiotic prophase I in mice. / Holt, Janet E.; Pye, Victoria; Boon, Evan; Stewart, Jessica L.; García-Higuera, Irene; Moreno, Sergio; Rodríguez, Rubén; Jones, Keith T.; McLaughlin, Eileen A.

In: Development (Cambridge), Vol. 141, No. 6, 15.03.2014, p. 1354-1365.

Research output: Contribution to journalArticle

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AB - Fizzy-related 1 (FZR1) is an activator of the Anaphase promoting complex/cyclosome (APC/C) and an important regulator of the mitotic cell division cycle. Using a germ-cell-specific conditional knockout model we examined its role in entry into meiosis and early meiotic events in both sexes. Loss of APC/CFZR1 activity in the male germline led to both a mitotic and a meiotic testicular defect resulting in infertility due to the absence of mature spermatozoa. Spermatogonia in the prepubertal testes of such mice had abnormal proliferation and delayed entry into meiosis. Although early recombination events were initiated, male germ cells failed to progress beyond zygotene and underwent apoptosis. Loss of APC/CFZR1 activity was associated with raised cyclin B1 levels, suggesting that CDK1 may trigger apoptosis. By contrast, female FZR1Δ mice were subfertile, with premature onset of ovarian failure by 5 months of age. Germ cell loss occurred embryonically in the ovary, around the time of the zygotenepachytene transition, similar to that observed in males. In addition, the transition of primordial follicles into the growing follicle pool in the neonatal ovary was abnormal, such that the primordial follicles were prematurely depleted. We conclude that APC/CFZR1 is an essential regulator of spermatogonial proliferation and early meiotic prophase I in both male and female germ cells and is therefore important in establishing the reproductive health of adult male and female mammals.

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Holt JE, Pye V, Boon E, Stewart JL, García-Higuera I, Moreno S et al. The APC/C activator FZR1 is essential for meiotic prophase I in mice. Development (Cambridge). 2014 Mar 15;141(6):1354-1365. https://doi.org/10.1242/dev.104828