Maternal CENP-C restores centromere symmetry in mammalian zygotes to ensure proper chromosome segregation

Catherine A Tower¹, Gabriel Manske², Emily L Ferrell³, Dilara N Anbarci¹, Kelsey Jorgensen⁴, Binbin Ma⁵, Mansour Aboelenain⁶, Rajesh Ranjan⁵, Saikat Chakraborty¹, Lindsay Moritz¹, Arunika Das⁷, Michele Boiani⁸, Ben E Black⁹, Shawn Chavez¹⁰, Erica E Marsh³, Ariella Shikanov¹¹, Karen Schindler¹², Xin Chen⁵, Saher Sue Hammoud¹³

Affiliations

¹ Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
² Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA; Cellular and Molecular Biology Graduate Program, University of Michigan, Ann Arbor, MI 48109, USA.
³ Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI 48109, USA.
⁴ Department of Anthropology, University of Kansas, Lawrence, KS 66044, USA.
⁵ Howard Hughes Medical Institute, Department of Biology, John Hopkins University, Baltimore, MD 21218, USA.
⁶ Department of Genetics, Rutgers University, Piscataway, NJ 08854, USA; Centre for Cell Biology, Institute of Cell Biology, University of Edinburgh, Edinburgh EH9 3BF, UK; Department of Theriogenology, Faculty of Veterinary Medicine, Mansoura University, Mansoura 35516, Egypt.
⁷ Department of Biomedical Sciences, Cornell University College of Veterinary Medicine, Ithaca, NY 14853, USA.
⁸ Max Planck Institute for Molecular Biomedicine, Department of Cell & Tissue Dynamics, Muenster 48149, Germany.
⁹ Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA 19104, USA.
¹⁰ Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Beaverton, OR 97006, USA; Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR 97239, USA; Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, OR 97239, USA; Department of Biomedical Engineering, Oregon Health and Science University, Portland, OR 97239, USA.
¹¹ Cellular and Molecular Biology Graduate Program, University of Michigan, Ann Arbor, MI 48109, USA; Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA.
¹² Department of Genetics, Rutgers University, Piscataway, NJ 08854, USA.
¹³ Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA; Cellular and Molecular Biology Graduate Program, University of Michigan, Ann Arbor, MI 48109, USA; Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Urology, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: hammou@umich.edu.

PMID: 40997799
PMCID: PMC12479092 (available on 2026-09-24)
DOI: 10.1016/j.devcel.2025.08.017

Maternal CENP-C restores centromere symmetry in mammalian zygotes to ensure proper chromosome segregation

Catherine A Tower et al. Dev Cell. 2025.

. 2025 Sep 24:S1534-5807(25)00537-4.

doi: 10.1016/j.devcel.2025.08.017. Online ahead of print.

Authors

Affiliations

¹ Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
² Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA; Cellular and Molecular Biology Graduate Program, University of Michigan, Ann Arbor, MI 48109, USA.
³ Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI 48109, USA.
⁴ Department of Anthropology, University of Kansas, Lawrence, KS 66044, USA.
⁵ Howard Hughes Medical Institute, Department of Biology, John Hopkins University, Baltimore, MD 21218, USA.
⁶ Department of Genetics, Rutgers University, Piscataway, NJ 08854, USA; Centre for Cell Biology, Institute of Cell Biology, University of Edinburgh, Edinburgh EH9 3BF, UK; Department of Theriogenology, Faculty of Veterinary Medicine, Mansoura University, Mansoura 35516, Egypt.
⁷ Department of Biomedical Sciences, Cornell University College of Veterinary Medicine, Ithaca, NY 14853, USA.
⁸ Max Planck Institute for Molecular Biomedicine, Department of Cell & Tissue Dynamics, Muenster 48149, Germany.
⁹ Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA 19104, USA.
¹⁰ Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Beaverton, OR 97006, USA; Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR 97239, USA; Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, OR 97239, USA; Department of Biomedical Engineering, Oregon Health and Science University, Portland, OR 97239, USA.
¹¹ Cellular and Molecular Biology Graduate Program, University of Michigan, Ann Arbor, MI 48109, USA; Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA.
¹² Department of Genetics, Rutgers University, Piscataway, NJ 08854, USA.
¹³ Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA; Cellular and Molecular Biology Graduate Program, University of Michigan, Ann Arbor, MI 48109, USA; Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Urology, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: hammou@umich.edu.

PMID: 40997799
PMCID: PMC12479092 (available on 2026-09-24)
DOI: 10.1016/j.devcel.2025.08.017

Abstract

Across metazoan species, the centromere-specific histone variant CENP-A is essential for accurate chromosome segregation, yet its regulation during the mammalian parental-to-zygote transition is poorly understood. To address this, we generated a CENP-A-mScarlet mouse model that revealed sex-specific dynamics: mature sperm retain 10% of the CENP-A levels present in MII oocytes. However, this difference is resolved in zygotes prior to the first mitosis, using maternally inherited cytoplasmic CENP-A. Notably, the increase in CENP-A at paternal centromeres is independent of sensing CENP-A asymmetry or the presence of maternal chromosomes. Instead, CENP-A equalization relies on the asymmetric recruitment of maternal CENP-C to paternal centromeres. Depletion of maternal CENP-A decreases total CENP-A in both pronuclei without disrupting equalization. In contrast, reducing maternal CENP-C or disruption of its dimerization function impairs CENP-A equalization and chromosome segregation. Therefore, maternal CENP-C acts as a key epigenetic regulator that resets centromeric symmetry at fertilization to preserve genome integrity.

Keywords: CENP-A; CENP-C; MIS18BP1; centromere; epigenetics; intergenerational; mouse; oocyte; sperm; zygote.

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Conflict of interest statement

Declaration of interests S.S.H. is on the Developmental Cell advisory board.

Update of

Maternal CENP-C restores centromere symmetry in mammalian zygotes to ensure proper chromosome segregation.
Tower CA, Manske G, Ferrell EL, Anbarci DN, Jorgensen K, Ma B, Aboelenain M, Ranjan R, Chakraborty S, Moritz L, Das A, Boiani M, Black BE, Chavez S, Marsh EE, Shikanov A, Schindler K, Chen X, Hammoud SS. Tower CA, et al. bioRxiv [Preprint]. 2025 Jul 28:2025.07.23.666394. doi: 10.1101/2025.07.23.666394. bioRxiv. 2025. Update in: Dev Cell. 2025 Sep 24:S1534-5807(25)00537-4. doi: 10.1016/j.devcel.2025.08.017. PMID: 40766472 Free PMC article. Updated. Preprint.

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Maternal CENP-C restores centromere symmetry in mammalian zygotes to ensure proper chromosome segregation

Affiliations

Maternal CENP-C restores centromere symmetry in mammalian zygotes to ensure proper chromosome segregation

Authors

Affiliations

Abstract

Conflict of interest statement

Update of

References

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Full Text Sources