# NIMA-like Kinase NEK1 as a Regulator of Mammalian Gametogenesis

> **NIH NIH R00** · MAGEE-WOMEN'S RES INST AND FOUNDATION · 2020 · $174,882

## Abstract

Project summary
Meiosis is a specialized cell division characterized by a single round of DNA replication followed by two rounds
of chromosome segregation, resulting in the formation of gametes. Cohesin is a chromosome-associated
multiprotein ring that maintains sister chromatid cohesion, and which is essential for accurate
chromosome/chromatid segregation. During meiosis, cohesin disassembly is particularly complicated by the
requirement for sequential loss of cohesion along the chromosome arms at the first meiotic division (MI) and
then at the centromere during the second meiotic division (MII). NIMA-like kinase 1 (NEK1) is a dual specific
serine/threonine and tyrosine kinase that is highly expressed in germ cells. Loss of NEK1 in mice leads to
retention of the cohesin subunit SMC3 on chromosome arms at MI and subsequent infertility. Cohesin removal
is orchestrated in two steps, first by “the prophase pathway”, followed by Separase-mediated cleavage of the
cohesin ring. The prophase pathway is defined by the stoichiometry between the Wings-apart-like protein
(WAPL) and Sororin, which compete for binding to PDS5B on the cohesin ring, but this pathway has not yet
been described in meiosis. My preliminary data reveal exciting roles for NEK1 in the regulation of cohesin
dynamics at MI, both directly at the level of the cohesin subunits, SMC3, RAD21L and REC8, and indirectly
through phosphorylation the PDS5B-WAPL complex. Furthermore, my studies have shown that NEK1 action
on the prophase pathway is mediated via Protein Phosphatase 1-gamma (PP1γ), which is a phosphotarget of
NEK1, and which binds and de-phoshphorylates WAPL. Moreover, my preliminary studies indicate that NEK1
also regulates a cascade of other NEK proteins to perform other roles in MI that are distinct from its activity on
cohesion dynamics. Thus, I hypothesize that NEK1 acts as master regulator of events in meiosis, primarily
playing a crucial role in the timing of cohesin removal at MI through its actions on critical components of the
prophase pathway, but also in orchestrating the actions of other NEK kinases. My long term goal is to elucidate
how NEK1 regulates cohesion removal at MI, but also to further characterize the role of NEK1 catalytic activity
in orchestrating downstream events at both meiotic divisions. Three specific aims are proposed: (1) To
elucidate the role of NEK1 in the phosphorylation of PP1γ, (2) To assess the importance of WAPL
phosphorylation on cohesion removal at MI and (3) To elucidate the function of NEK1 as a master regulator of
the NEK family during meiosis. These experiments will provide a novel and exciting data that describes, for the
first time, the the role of NEK1 in the regulation of cohesin removal during the prophase pathway in meiosis.
The applicant, Dr. Brieño-Enríquez, is an MD, PhD with considerable experience in the field of gamete biology.
The applicant has studied distinct process of gamete biology in humans and mice, with a goal to unde...

## Key facts

- **NIH application ID:** 9902491
- **Project number:** 5R00HD090289-04
- **Recipient organization:** MAGEE-WOMEN'S RES INST AND FOUNDATION
- **Principal Investigator:** MIGUEL ANGEL BRIENO-ENRIQUEZ
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $174,882
- **Award type:** 5
- **Project period:** 2019-03-27 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9902491

## Citation

> US National Institutes of Health, RePORTER application 9902491, NIMA-like Kinase NEK1 as a Regulator of Mammalian Gametogenesis (5R00HD090289-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9902491. Licensed CC0.

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