# Regulation of Centrosome Biogenesis During Mammalian Spermatogenesis

> **NIH NIH F31** · JOHNS HOPKINS UNIVERSITY · 2024 · $48,974

## Abstract

Infertility effects around 15% of couples that are of reproductive age worldwide. Issues relating to infertility often
arise due to errors in the process of meiosis, the specialized cell division where a single diploid cell gives rise to
four haploid gametes. The general sequence of events in meiosis includes one round of DNA replication, the
separation of homologous chromosomes (meiosis I), and then the separation of sister chromatids (meiosis II).
During the process of chromosome segregation, the cell organizes bipolar spindles to evenly divide the genetic
material. Like most mitotically dividing cells, spermatocytes rely on the centrosome to be the microtubule
organizing center responsible for the formation of bipolar spindles. The centrosome consists of two centrioles
and associated proteins known as pericentriolar material (PCM). Centrioles are cylindrical organelles that exist
in pairs, one centriole oriented perpendicular to the other. The PCM that surrounds them consists of ordered,
dynamic proteins that are necessary for cellular functions such as protein degradation, organelle trafficking, and
spindle assembly. The PCM also acts as the spindle organizing center by concentrating the γ-tubulin that serves
as nucleation sites for assembling the microtubules necessary for bipolar spindle formation and chromosome
segregation. During cellular division, centriole duplication occurs. Polo-like kinase 4 (PLK4) is responsible for
this duplication event in mitosis. PLK4 is regulated through autophosphorylation and proteasomal degradation
to ensure centriole duplication only occurs once during the cell cycle. However, in meiosis the cell must undergo
centriole duplication twice and centriole duplication is no longer coupled with DNA synthesis, but rather takes
place during prophase I and interkinesis. Furthermore, PLK4 protein levels remain high during spermatogenesis
and its activity is likely regulated by a novel mechanism. Because of this added complexity, the role of PLK4 in
relationship to centriole duplication during meiosis is not yet understood. To determine the role of PLK4 in
meiosis, conditional knockout (cKO) and overexpression (OE) mouse models, which allow for depletion or
upregulation of PLK4 in early prophase spermatocytes, are utilized. In the Plk4 cKO model, due to the lack of
functional PLK4, centrioles fail to duplicate, and the spermatocytes enter meiosis I with a single centrosome. In
contrast, centrioles are over duplicated in the Plk4 OE model. It is our goal to utilize these models to further
characterize the role of PLK4 as well as elucidate other regulatory mechanisms and components required for
centrosome biogenesis during mammalian spermatogenesis. As centrosome biogenesis is critical for
chromosome segregation during spermatogenesis, and centrioles are required for sperm flagella formation, our
studies will contribute to understanding causes of infertility and gamete aneuploidy. We will address the following
aims in th...

## Key facts

- **NIH application ID:** 10889055
- **Project number:** 5F31HD111265-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Marnie Skinner
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 5
- **Project period:** 2023-07-17 → 2025-10-16

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10889055

## Citation

> US National Institutes of Health, RePORTER application 10889055, Regulation of Centrosome Biogenesis During Mammalian Spermatogenesis (5F31HD111265-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10889055. Licensed CC0.

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