Novel role of FOXO, a transcription factor, in egg cell development

Banya Kar

A recent study by researchers at the National Institute of Immunology (NII), New Delhi, led by Arnab Mukhopadhyay, used C. elegans to show how damage to somatic tissues in the body can influence the development of reproductive cells — particularly eggs. They found that DNA damage signals from uterine tissue can stop egg cell formation through a key FOXO transcription factor, which is a highly conserved protein across different organisms.

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When DNA damage is inflicted on worms having low insulin signaling, egg cell development fails to proceed and no egg cells are produced. Picture Credit: Arnab Mukhopadhyay.

Living organisms face a multitude of challenges that can harm their genetic code and impact the fitness of future generations. To safeguard against this, organisms use a set of mechanisms called the DNA Damage Response (DDR) which helps in repairing DNA damage or triggering cell death when the damage is too severe. While we understand how reproductive cells handle damage, Arnab Mukhopadhyay and his team at the National Institute of Immunology, New Delhi, asked a fundamental question: 

how does DNA damage in other body tissues affect reproductive cells and their development? 

Mukhopadhyay’s team studies C. elegans, a tiny nematode or worm, to learn about the molecular mechanisms underlying longevity in organisms. They are interested in understanding how pathways that sense nutrients, the link between diet and aging, affect egg cell production and reproductive age. 

The team discovered that cdk-12, a gene that helps in copying information from DNA to RNA (transcription), is crucial in maintaining genomic integrity. Reducing the activity of CDK-12 weakens the DDR, leaving the genetic material vulnerable to damage, which is similar to what happens in mammals. In their experiments with C. elegans, inducing DNA damage in the worm’s body tissues resulted in poor-quality egg cells and increased infertility in the worms. What happens in the worms that have high resilience to stress and delayed reproductive aging? Is their germline quality equally susceptible to the somatic DNA damage or do they have mechanisms to protect their offspring better”, adds Mukhopadhyay.

Digging deeper, the researchers used worms with a genetic mutation that leads to lower insulin signaling, mimicking a situation of reduced nutrient availability. Lowering insulin signalling increased the worm’s lifespan, stress resistance, and improved the quality of eggs. Under low insulin signaling, reducing cdk-12 activated FOXO/DAF-16 (a key transcription factor) prevented egg formation, consequently avoiding the production of faulty offspring during compromised genomic integrity. 

Molecular Aging Research Group, National Institute of Immunology, New Delhi. Picture Credit: Arnab Mukhopadhyay team.
Molecular Aging Research Group, National Institute of Immunology, New Delhi. Picture Credit: Arnab Mukhopadhyay team.

In the words of Anindya Ghosh Roy, Scientist & Professor, National Brain Research Centre, Manesar, The authors discovered a signaling mechanism between uterine tissues and germline involving Insulin signaling, controlling the quality of the oocyte during the DNA damage response (DDR). This opens up a new avenue to dissect the crosstalk between the somatic and germline tissues in detail.”

This study also showed that when DNA damage occurred in somatic tissues, FOXO/DAF-16 stopped germ cell development by reducing a signaling pathway called ERK/MPK‑1. This signaling pathway takes crucial decisions during the progression of egg cell development. Further, the group found that reducing cdk-12 specifically in the uterine tissues of the worm led to this arrest in germ cell development. 

K. Subramaniam, Professor, Department of Biotechnology, Indian Institute of Technology Madras appreciates the authors’ efforts to reveal a novel role of FOXO (DAF-16) as the soma signal sensor in the regulation of oocyte/​egg cell development”. He adds rather hopefully, 

It will also be interesting to test if this germline-soma communication (i.e., between cells responsible for passing heritable information and rest of the body) of DDR has been conserved during evolution.

The study emphasised that defects in DDR can result in reduced fitness of offspring, infertility, and chromosomal abnormalities. Activated FOXO/DAF-16 was identified as a key guardian preserving the quality of germ cells and the fitness of future generations when somatic DNA damage occurs. The work also highlights the crosstalk between somatic and germline cells to tackle threats to genomic integrity. 

The lead authors, Gautam Sarkar and Umanshi Rautela, explain, From an evolutionary perspective, such inter-tissue crosstalk likely helps an organism sense intrinsic or extrinsic stresses more efficiently and accurately. This may aid in ensuring optimal survival as well as fitness across generations.”

Looking ahead, the research group plans to investigate how FOXO regulates the development of egg and sperm cells from outside of the cells where it is expressed. This study is an important step in understanding how nutrient-sensing pathways regulate developmental processes in response to environmental stressors like DNA damage.

Written By

Science Communication and Public Relations, National Institute of Immunology