Embryonic diapause can be induced by nutrient deprivation, but the molecular mechanisms underpinning this process are unclear. A new paper in Development shows that protein and carbohydrate depletion can trigger embryonic diapause via the nutrient sensors Gator1 and Tsc2. To learn more about the story behind the paper, we caught up with first author Jiajia Ye and corresponding author Qiang Sun, professor and director of the Non-Human Primate Research Facility at the Institute of Neuroscience, Chinese Academy of Sciences.
Qiang Sun (left) and Jiajia Ye (right)
Qiang, can you give us your scientific biography and the questions your lab is trying to answer?
QS: The main focus of our laboratory and my research is the development of non-human primate gene-modified models and the exploration of reproductive physiology, assisted reproduction, embryo development and stem cell technology.
Jiajia, how did you come to work in Qiang's lab and what drives your research today?
JY: In 2018, I began my master's and doctoral research training at the Institute of Neuroscience. Dr Sun's publication on cloned monkeys catalysed my desire to join their laboratory for further studies. I am honored to have been selected to join Dr Sun's laboratory for research training, under the mutual selection process between students and mentors at the institute.
I am motivated by the opportunity to contribute to the advancement of embryonic development and make meaningful impacts on society. Most animal experiments are aimed at addressing issues in humans, and our study conducted on mice is just the beginning.
Before your work, what was already known about how nutrient stress induces embryonic diapause?
QS & JY: The roe deer is the earliest known animal to exhibit embryonic diapause. The gestation period for roe deer is 8 months, but the embryos only require 3 months from implantation to birth. Most of the time that the embryos are in a state of diapause (from August to January in the Northern Hemisphere) coincides with cold weather and food scarcity. The consensus is that this embryonic diapause ensures that the fawns are born at the most opportune time for survival.
Recent studies have shown that roe deer exhibit decreased protein abundance in uterine fluid during embryonic diapause, and that this increases during activation. However, these results only indicate correlation between nutrition and embryonic diapause, rather than proving causality.
Can you give us the key results of the paper in a paragraph?
QS & JY: During environmental stresses, the mouse uterine microenvironment experiences protein and carbohydrate deprivation. Protein and carbohydrate depletion activate Gator1 and Tsc2, respectively, in the blastocyst, ultimately leading to embryonic diapause.
How does your study expand our understanding of the role of mTOR in diapause?
QS & JY: The molecular mechanism (both up- and downstream) of mTOR is well known in mammal cell lines. Our study uncovers the essential role of Gator1 and Tsc2, which are known to sit upstream of mTORC1 in fibroblasts, in mouse diapause induction. In fact, we have examined other mTORC1 upstream factors, such as P27 and Axin, but their mutation did not affect diapause induction. Therefore, we think our study expands the mTORC1-regulated mechanism in the embryo and elucidates how environmental stresses inhibit mTORC1 activity.
Our study expands the mTORC1-regulated mechanism in the embryo and elucidates how environmental stresses inhibit mTORC1 activity
Immunofluorescence image of a murine diapaused blastocyst. Diapause was induced by medium with nutrient deprivation. The treatment prolongs the blastocyst survival time for a week in vitro. ZO-1 is shown in green, Oct4 in red and DAPI in blue. Photo courtesy of Jiajia Ye.
Do you think your findings will apply to other mammalian species?
QS & JY: Yes. As we say above, roe deer also decrease protein abundance in uterine fluid during embryonic diapause, which suggests that nutrient deprivation might also be inducing embryonic diapause in roe deer. Moreover, embryonic diapause is an advantageous trait for mammalian reproduction, allowing for the preservation of offspring during evolution. Therefore, many speculate that mammalian species currently lacking embryonic diapause may have experienced changes in their survival environment (such as climate warming or species migration), leading to inconspicuous or shorter durations of embryonic diapause. However, they may still retain the molecular pathways associated with embryonic diapause in their embryos. Therefore, we think our study might apply to primates.
When doing the research, did you have any particular result or eureka moment that has stuck with you?
JY: After obtaining the result that pre-implantation maternal starvation induces mouse embryonic diapause, I wanted to know how maternal starvation leads to this result. After consulting the literature, the idea of nutrient deprivation suddenly struck me like a bolt to my brain. I am very fortunate that I did not ignore this idea.
And what about the flipside: any moments of frustration or despair?
JY: The journey of research is often filled with countless frustrations and occasional sparks of surprise. Ovariectomy-induced embryonic diapause is a commonly used method in the field, but the protocols described in many papers vary. When I attempted the method described in one paper for the first time, performing ovariectomy on mice and administering daily progesterone to maintain embryonic diapause, I sacrificed the mice after 3 days of surgery and found that all embryos in the mice had implanted. I felt frustrated after investing so much time, effort, and sacrificing the lives of several mice without obtaining any meaningful results.
Jiajia, what is next for you after this paper?
JY: To further understand why nutrient deprivation can induce mouse embryonic diapause (via approaches such as exploring the pathways downstream of mTORC1 and the reversibility of diapause) and whether our study can apply to primates.
Qiang, where will this story take your lab next?
QS: We are interested in finding out if primates also experience the embryonic diapause phenomenon.
Finally, let's move outside the lab – what do you like to do in your spare time?
QS: Running.
JY: Exercising and enjoying good food are the best ways for me to relieve stress. Riding my bike to find delicious food is my favourite hobby in my spare time.
J.Y. & Q.S.: Institute of Neuroscience, CAS Key Laboratory of Primate Neurobiology, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China.
J.Y.: Shanghai Center for Brain Science and Brain-Inspired Technology, Shanghai 201210, China and University of Chinese Academy of Sciences, Beijing 100049, China.
E-mail: [email protected]
