Researchers at University of Texas Southwestern Medical Center have identified two proteins in a foetus’ lungs responsible for initiating the labour process, providing potential new targets for preventing preterm birth.

Previous studies have suggested that signals from the foetus initiate the birth process, but the precise molecular mechanisms that lead to labour remained unclear. UT Southwestern biochemists studying mouse models found that the two proteins − steroid receptor coactivators 1 and 2 (SRC-1 and SRC-2) – control genes for pulmonary surfactant components that promote the initiation of labour. Surfactant is a substance released from the foetus’ lungs just prior to birth that is essential for normal breathing outside the womb.

“Our study provides compelling evidence that the foetus regulates the timing of its birth, and that this control occurs after these two gene regulatory proteins − SRC-1 and SRC-2 − increase the production of surfactant components, surfactant protein A and platelet activating factor,” said senior author Dr. Carole Mendelson, Professor of Biochemistry, and Obstetrics and Gynecology at UT Southwestern.

“By understanding the factors and pathways that initiate normal-term labour at 40 weeks, we can gain more insight into how to prevent preterm labour,” said Dr. Mendelson, Director of the North Texas March of Dimes Birth Defects Center at UT Southwestern.

Each year about one in every nine infants in the United States is born preterm (before 37 weeks), according to the Centers for Disease Control and Prevention. Premature birth can cause brain haemorrhage and respiratory distress for babies, as well as long-term conditions such as cerebral palsy, chronic lung disease, and impaired vision.

The study, which appears in the Journal of Clinical Investigation, was supported by the National Institutes of Health and a Prematurity Research Initiative grant from the March of Dimes Foundation.

UT Southwestern researchers found that the proteins SRC-1 and SRC-2 activate genes inside the foetus’ lungs near full term, resulting in an increased production of surfactant components, surfactant protein A (SP-A), and platelet-activating factor (PAF). Both SP-A and PAF are then secreted by the foetus’ lungs into the amniotic fluid, leading to an inflammatory response in the mother’s uterus that initiates labour.

The current study showed that a deficiency of both SRC-1 and SRC-2 inside the foetus’ lungs drastically decreased the production of SP-A and PAF, causing a one- to two-day labour delay in mouse models, comparable to a three- to four-week labour delay in women.

Researchers further found that injecting either SP-A or PAF into the amniotic fluid of the deficient mice allowed the mothers to deliver on time. Together, the findings further define the underlying molecular mechanisms by which foetuses control the timing of birth.

Future research will include defining how foetal signals are transmitted to the mother’s uterus, and relating these findings to the causes of preterm labour.

The study was conducted with current and former UT Southwestern researchers, including first author Dr. Lu Gao; Dr. Elizabeth Rabbitt; Dr. Jennifer Condon; Dr. Nora Renthal; Dr. John Johnston; Dr. Matthew Mitsche; and researchers from the Institut de Génétique et de Biologie Moléculaire et Cellulaire, France, and Baylor College of Medicine in Houston.

Dr. Mendelson’s laboratory is part of UT Southwestern’s Cecil H. and Ida Green Center for Reproductive Biology Sciences, which promotes and supports cutting-edge, integrative, and collaborative basic research in female reproductive biology, with a focus on signaling, gene regulation, and genome function.

(Source: University of Texas – Southwestern, Journal of Clinical Investigation)

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