A molecular alarm clock awakens resting ovules

At the start of reproductive life an ovary contains, on average, several thousands of immature ovules in a resting state that can last for several decades. But how does each resting ovule know that it is time to prepare for ovulation? In a study published in the latest issue of Nature Communications*, researchers at Instituto Gulbenkian de Ciencia (IGC; Portugal), at University of Algarve (Portugal), and at University at Albany (USA) discovered in the fruit fly a molecular “alarm clock” that tells resting ovules when is the right time to wake up. Defects in this alarm clock result in female fertility problems.
During their resting period, ovules turn off their genes to enter an almost hibernation-like state. When they wake up, they need to turn their genes back on so they can grow and become ready for ovulation. The research team led by Rui Martinho, from the Center for Biomedical Research at University of Algarve and from Instituto Gulbenkian de Ciencia, and Prashanth Rangan, from University at Albany, discovered that the timing of turning the genes back on is programmed directly into the chromosomes of the ovule. To uncover this mechanism, the research team conducted a series of genetic experiments in fruit flies (Drosophila melanogaster). Paulo Navarro-Costa, first co-author of this study and researcher at the IGC explains: “Similarly to humans, fruit fly ovules also have a resting period during meiosis – the specialized cell division required for the formation of healthy reproductive cells. Therefore, this organism could help us understanding exactly how the ovule is able to turn back on its genes at the right time, a biological mystery until now.”
The results of the research team revealed the ovules keep track of time during meiosis using a process similar to a molecular “alarm clock”. Rui Martinho clarifies the mechanism: “When ovules begin to form, a protein called dKDM5 modifies the chromosomes in a way that they can only activate their genes at the right time. If this alarm clock is incorrectly set, for example due to defects in the dKDM5 protein, females become infertile because their ovules fail to complete meiosis.”
An unexpected property of this new molecular alarm clock is that it is set at early stages of ovule formation, long before the cell needs to be awakened. “These results illustrate just how important for female fertility is the early life of the ovule. For instance, in the case of humans, the early stages of ovule formation occur before women are born, while they are still in their mother’s womb. This prenatal development period is therefore critical for the future formation of healthy reproductive cells”, says Paulo Navarro-Costa.
This study was conducted at Instituto Gulbenkian de Ciência and at University at Albany, and was funded by Fundação para a Ciência e a Tecnologia (Portugal), and the National Institutes of Health (USA).
*Paulo Navarro-Costa, Alicia McCarthy, Pedro Prudêncio, Christina Greer, Leonardo G. Guilgur, Jörg D. Becker, Julie Secombe, Prashanth Rangan and Rui G. Martinho. (2016) “Early programming of the oocyte epigenome temporally controls late prophase I transcription and chromatin remodeling“, Nature Communications. DOI: 10.1038/NCOMMS12331

CBMR researchers develop innovative research for the treatment of leukemia

CBMR researchers and their collaborators discovered that normal, nonmalignant cells use a protein involved in cell-to-cell communication to foster leukaemia development.

T-cell acute lymphoblastic leukaemia (T-ALL) is an aggressive disease that affects mainly children and adolescents, and despite great therapeutic improvements, many patients suffer lifelong sequels while others develop chemotherapeutic-resistant disease relapse and do not survive.

To understand how nonmalignant cells contribute to T-ALL development, CBMR scientists studied proteins known to be involved in cellular communication in the immune system, the lymphotoxin proteins.

The lymphotoxin genes were found to be highly expressed in a large subset of T-ALL patient samples and cell lines, so to study the functional role of lymphotoxin in this disease the researchers used a transgenic mouse model. Like human T-ALL, T-cell leukaemia in these mice also displayed high levels of lymphotoxin expression. More importantly, genetic inactivation of the lymphotoxin-β receptor in the transgenic mouse model not only delayed the initial appearance of malignant cells in the thymus, the organ where disease originates, but also prolonged mouse survival.

Treatment of transgenic mice with a molecule inhibiting lymphotoxin-β receptor delayed T-ALL, so these findings suggest that interfering with lymphotoxin function may be a potential strategy for T-ALL treatment

This study can be consulted here in British Journal of Haematolgy.


CBMR researchers found one of the mechanisms that drives protein fibrillation

Several neurodegenerative diseases such as Alzheimer’s and prion diseases result from protein misfolding leading to the accumulation of protein aggregates shaped as amyloid fibrils. Using as model a simple protein we confirmed one of the mechanisms that drives protein fibrillation and more importantly we have elucidated how a simple sugar such as sucrose can delay protein fibrillation by compacting the globular structure of the protein.

Read the paper here.


Our research is in the radio

Rui Martinho, CBMR researcher, gave an interview to the radio program “Cientificamente” about his last project.

Listen and learn more about his innovative research.