CKS1 Germ Line Exclusion Is Essential for the Transition from Meiosis to Early Embryonic Development

Zdenka Ellederova; Sonia Del Rincon; Marketa Koncicka; Andrej Susor; Michal Kubelka; Dahui Sun; Charles Spruck

doi:10.1128/MCB.00590-18

CKS1 Germ Line Exclusion Is Essential for the Transition from Meiosis to Early Embryonic Development

Mol Cell Biol. 2019 Jun 13;39(13):e00590-18. doi: 10.1128/MCB.00590-18. Print 2019 Jul 1.

Authors

Zdenka Ellederova^{1

2}, Sonia Del Rincon^{1

3}, Marketa Koncicka^{4

5}, Andrej Susor⁴, Michal Kubelka⁴, Dahui Sun¹, Charles Spruck⁶

Affiliations

¹ Tumor Initiation and Maintenance Program, Sanford | Burnham | Prebys Medical Discovery Institute, La Jolla, California, USA.
² Laboratory of Cell Regeneration and Plasticity, Institute of Animal Physiology and Genetics, Czech Academy of Science, Libechov, Czech Republic.
³ Gerald Bronfman Department of Oncology, McGill University Lady Davis Institute, Segal Cancer Centre-Jewish General Hospital, Montreal, Quebec, Canada.
⁴ Laboratory of Biochemistry and Molecular Biology of Germ Cells, Institute of Animal Physiology and Genetics, Czech Academy of Science, Libechov, Czech Republic.
⁵ Department of Cell Biology, Faculty of Science, Charles University, Prague, Czech Republic.
⁶ Tumor Initiation and Maintenance Program, Sanford | Burnham | Prebys Medical Discovery Institute, La Jolla, California, USA [email protected].

Abstract

Cell division cycle (Cdc) kinase subunit (CKS) proteins bind cyclin-dependent kinases (CDKs) and play important roles in cell division control and development, though their precise molecular functions are not fully understood. Mammals express two closely related paralogs called CKS1 and CKS2, but only CKS2 is expressed in the germ line, indicating that it is solely responsible for regulating CDK functions in meiosis. Using cks2^-/- knockout mice, we show that CKS2 is a crucial regulator of maturation-promoting factor (MPF; CDK1-cyclin A/B) activity in meiosis. cks2^-/- oocytes display reduced and delayed MPF activity during meiotic progression, leading to defects in germinal vesicle breakdown (GVBD), anaphase-promoting complex/cyclosome (APC/C) activation, and meiotic spindle assembly. cks2^-/- germ cells express significantly reduced levels of the MPF components CDK1 and cyclins A1/B1. Additionally, injection of MPF plus CKS2, but not MPF alone, restored normal GVBD in cks2^-/- oocytes, demonstrating that GVBD is driven by a CKS2-dependent function of MPF. Moreover, we generated cks2^cks1/cks1 knock-in mice and found that CKS1 can compensate for CKS2 in meiosis in vivo, but homozygous embryos arrested development at the 2- to 5-cell stage. Collectively, our results show that CKS2 is a crucial regulator of MPF functions in meiosis and that its paralog, CKS1, must be excluded from the germ line for proper embryonic development.

Keywords: CKS; cyclin-dependent kinases; developmental biology; meiosis.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
CDC2-CDC28 Kinases / genetics*
CDC2-CDC28 Kinases / metabolism
Cell Cycle Proteins / genetics*
Cell Cycle Proteins / metabolism
Embryonic Development*
Female
Gene Knock-In Techniques
Male
Maturation-Promoting Factor / metabolism
Meiosis
Mesothelin
Mice
Mice, Knockout
Oocytes / cytology*
Oocytes / metabolism

Substances

Cell Cycle Proteins
Msln protein, mouse
CDC2-CDC28 Kinases
Cks1 protein, mouse
Cks2 protein, mouse
Maturation-Promoting Factor
Mesothelin

Grants and funding

R01 HD049539/HD/NICHD NIH HHS/United States