# Mechanisms of chromosome motility during mammalian meiosis

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $479,661

## Abstract

Mechanisms of chromosome motility during mammalian meiosis
Project Summary/Abstract
Meiosis is a specialized form of cell division of the germline that produces haploid gametes essential for sexual
reproduction. A critical step in meiosis is the recombination between homologous chromosomes, also called
meiotic crossover, required for the proper segregation of chromosomes into the daughter cells. Imperfect
segregation prevents progression through meiosis and is a risk factor for infertility and miscarriage. A detailed
understanding of meiotic crossover will enhance the knowledge of meiosis and hold implications for human
reproductive biology. Essential to meiotic crossover is a remodeling process in the cell that involves connecting
chromosomes in the nucleus to dynein in the cytosol via protein-protein interactions spanning the nuclear
envelope. This event allows dynein to move all chromosomes along the nuclear envelope to facilitate the
search and pairing of homologous chromosomes for undergoing crossover. A key player in this process is the
SUN1-KASH5 LINC complex that spans the nuclear envelope to link chromosomes to dynein. Despite the
importance of chromosome-nuclear envelope tethering and motility in mammalian meiosis, a molecular
mechanism for this phenomenon is still lacking. Understanding how SUN1-KASH5 performs its meiosis-
specific function will generate new knowledge to improve the diagnosis and treatment of fertility disorders.
Using a multi-disciplinary approach that includes biochemical/biophysical methods, fixed and live-cell
microscopy, single-molecule TIRF microscopy, membrane protein reconstitution, and a specialized mouse
meiosis model system, this proposal aims to understand how dynein moves chromosomes to facilitate
homolog pairing during meiosis. Aim 1 of the proposal will determine the structural basis, the dynamics, and
the meiosis-specificity of the KASH5-dynein interaction instrumental to crossover. Interrogation in mouse
spermatocytes will complement the in vitro studies to reveal how the KASH5-dynein interaction helps uphold
mouse fertility. Aim 2 of this proposal will determine the higher-order structures adopted by SUN1-KASH5 at
the nuclear envelope and how they enable cytosolic dynein forces to move entire chromosomes in the nucleus.
This Aim and the grant proposal culminate in the dissection of the molecular mechanism underlying infertility in
humans caused by a mutation in the gene encoding KASH5. The proposed studies will reveal how dynein and
LINC complexes come together to facilitate the essential process of crossover during mammalian meiosis.

## Key facts

- **NIH application ID:** 10442797
- **Project number:** 1R01HD108809-01A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Jayakrishnan Nandakumar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $479,661
- **Award type:** 1
- **Project period:** 2022-08-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10442797

## Citation

> US National Institutes of Health, RePORTER application 10442797, Mechanisms of chromosome motility during mammalian meiosis (1R01HD108809-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10442797. Licensed CC0.

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