Previous work has suggested that problems with placental development might lead to congenital heart defects. However, little is known about the mechanisms that might underpin this relationship between the placenta and the heart. A new paper in Development leverages conditional mouse knockouts to explore this link in detail. To learn more about the story behind the paper, we caught up with first author Wenli Fan and corresponding author Zhongzhou Yang, a Professor at Nanjing University Medical School, China.
Zhongzhou Yang (left) and Wenli Fan (right)
Zhongzhou, what questions are your lab trying to answer?
ZY: In general, we are addressing the regulatory mechanisms of heart development in order to understand the pathogenesis of human congenital heart diseases (CHDs). In particular, we are focused on the development of the second heart field (SHF, a population of cardiac progenitors) and on cardiac outflow tract (OFT) septation. The SHF makes a big contribution to OFT morphogenesis and septation, and defective OFT septation causes serious, complex CHDs, including conotruncal defects. A better understanding of OFT septation would lead to effective prevention and treatment of CHDs in the future.
Wenli, how did you come to work in Zhongzhou's lab and what drives your research today?
WF: After my internship and rotations in several labs, I ultimately decided to stay in Zhongzhou's lab because of my keen interest in cardiovascular development and diseases. This summer, I finished my PhD studies, which took nearly 6 years and trained me in scientific thinking and implementation. Now, my research is motivated by improving the understanding of the placental-organ axis and of developmental biology to guide the design of potential therapeutics.
Before your work, what was already known about how the placenta might affect heart development?
ZY & WF: The concept of the placenta–heart axis was first proposed in 1999, in a mouse genetic study that aimed to decipher the role of the peroxisome proliferator activated receptor gamma gene (Pparg) in embryonic development. The authors found that Pparg knockout mice had heart defects, and they attributed these defects to placental malformation. This concept was reinforced by a subsequent study in which deletion of the mitogen-activated protein kinase 14 gene (Mapk14/p38a) impaired placental development, leading to embryonic heart defects. In both studies, embryonic heart development was safeguarded in the mutant mice via tetraploid rescue techniques that restored proper placental development. Since then, a rapidly increasing number of studies using gene knockout mice have supported the idea that the placenta is involved in the regulation of embryonic heart development, but we don't understand the molecular mechanisms that underpin this role.
Can you give us the key results of the paper in a paragraph?
ZY & WF: We showed that Slc25a1 knockout mice exhibit both heart defects and placental malformation. We went on to generate a placental-specific Slc25a1 knockout, which recapitulated these phenotypes. By contrast, a cardiac-specific Slc25a1 knockout showed little effect on heart development. Single-cell sequencing of the Slc25a1 knockouts revealed trophoblast developmental abnormalities, and RNA-sequencing uncovered a substantial reduction of pregnancy-specific glycoproteins (PSGs), including PSG1. Administration of PSG1 to pregnant mice partially rescued placental and heart defects.
Why did you decide to focus on SLC25A1?
ZY & WF: To better understand human CHDs, we chose to work on the 22q11.2 deletion syndrome (also known as DiGeorge syndrome), where the majority of patients show CHDs. Among the ∼50 genes that are deleted in 22q11.2 deletion syndrome, around 10 genes have functions in the mitochondria. We therefore hypothesized that mitochondrial metabolic defects might contribute to CHDs. Slc25a1 is one such mitochondrial gene and so we decided to study its role in heart development.
Do you think your study will have implications for treating congenital heart defects in the future?
ZY & WF: In this study, we uncovered that administration of recombinant human PSG1 to pregnant mice improves placental and heart defects of the Slc25a1 mutant mice. This suggests that PSG1 might become a potentially effective drug to help improve placental and heart development of the fetus in the uterus.
PSG1 might become a potentially effective drug to help improve placental and heart development of the fetus in the uterus
Fluorescence microscopy image of a mouse placental section at embryonic day 12.5 (mouse line: Elf5-Cre; mTmG). Cre-positive cells (mainly the spongiotrophoblast cells and some labyrinth trophoblast cells) are in cyan and all other cells are in red.
When doing the research, did you have any particular result or eureka moment that has stuck with you?
WF: There were two eureka moments. The first eureka moment was when I found that all the Slc25a1 knockout mice displayed severe heart and neural defects, because I realized that this gene was indeed important for organ development. Then, the second eureka moment occurred when I dissected the placental-specific Slc25a1 knockout mice and found that the heart defects were recapitulated. This meant that SLC25A1 functions in the placenta to modulate heart development.
And what about the flipside: any moments of frustration or despair?
WF: Originally, we thought that SLC25A1 ought to have a crucial role in embryonic development, and that the cardiac-specific Slc25a1 knockout mice should demonstrate heart defects. However, I failed to detect heart abnormalities after dissecting several cardiac-specific Slc25a1 knockout mice, which caused me to worry a lot.
Why did you choose to submit this paper to Development?
ZY & WF: We read many papers that were published in Development during the past 30 years to learn about heart development and developmental biology, and these papers impressed us tremendously. The studies are of high quality and the results are invaluable. So, we regard Development as an esteemed journal. In addition, the editors are internationally renowned scientists who care deeply about the quality of the manuscript and know the research field. They handle the manuscripts in a timely manner. We, as a scientific community, have a responsibility to support this journal.
Wenli, what is next for you after this paper?
WF: I have started my postdoctoral research in reproductive biology, and I want to figure out how SLC25A1 in the placenta regulates neural tube closure.
Zhongzhou, where will this story take your lab next?
ZY: We will test more PSG proteins to see whether they can improve placental and heart development. Meanwhile, we will try to enhance our understanding of how the placenta regulates heart development by using more mouse models.
Finally, let's move outside the lab – what do you like to do in your spare time?
ZY: My PhD mentor, Dr Brian A. Hemmings FRS, used to tell us that half of science is communication. I would like to extend this point to say that half of our life is communication. So I like interactions with different people. For instance, I like going to rural areas/mountains to visit the local people in the villages, to learn how they make living there, and to understand their culture and wisdom. Alongside this, I like writing essays to convey my thoughts from a scientific conference or from visiting a village, town or city.
WF: In my spare time, I enjoy wandering around in the parks, which gives me the opportunity to relax, appreciate nature and clear my mind.
MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research, Center State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University Medical School, Nanjing 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University Medical School, Nanjing 210093, China.
E-mail: [email protected]
