Developmental Cell: Interprets new patterns of anteroposterior axis generation of embryos

The establishment of anterior-posterior axis (AP axis) is an important event in the development of mammalian embryos, and abnormalities in this process will lead to development failure and miscarriage
after implantation.
After implantation, the distal visceral endoderm (DVE) of the mouse embryo migrates unilaterally from the distal end to the embryo, and then locates on the anterior side of the embryo to form the anterior visceral endoderm (AVE).

The signaling molecules released by AVE act on the adjacent epiblast (EPI) to promote its specialization with the characteristics of the anterior side of the embryonic body, while the contralateral EPI is specialized to form the original strip because it is far from the AVE signal, and the anterior and posterior axis of the embryo is formally established
。 DVE and AVE are key cell populations in the process of anterior and posterior axis formation, and classical theory tends to believe that they are the two states of the same type of cells in the process of cell migration, that is, DVE is the precursor cell of AVE; In recent years, studies have also proposed that DVE and AVE are two different types of cells that exist at the same time, and AVE may be derived from non-DVE cells
.
Therefore, the specific origin and specialization mode of DVE and AVE, as well as the corresponding molecular regulation laws, need to be further revealed
.

Zhou Fan's research group from the School of Life Sciences of Tsinghua University published a research paper
entitled "Decoding anterior-posterior axis emergence among mouse, monkey, and human embryos" online in the journal Developmental Cell 。 This study combines high-precision omics, time-quasi-analysis, spatial distribution verification and other systems, and finds that the key cell populations DVE and AVE formed by the anterior and anteroposterior axes of mice have their own independent origin and developmental trajectories.
Cross-species comparison showed that non-human primates and human embryos contained only AVE cells during anteroposterior axis formation.
Existing stem cell induction/remodeling-based embryo-like models do not contain anteroposterior axis-related cell populations
.

In order to analyze the origin and development patterns of two key cell populations during the formation of the anteroposterior axis of embryos, the authors combined single-cell omics analysis and time-quasi-time prediction to find that DVE and AVE have independent preimplantation origins during the anterior and posterior axis formation of mouse embryos, and gradually mature and specialized
along their respective developmental trajectories after implantation 。 Combining spatial transcriptome and novel marker gene mining, the authors found that two groups of cells went through 4 representative stages, starting from the blastocyst stage before implantation: pro-DVE-> pre-DVE-> early-DVE-> late-DVE; pro-AVE-> pre-AVE-> early-AVE-> late-AVE, each stage of the cell population has a unique gene expression pattern
.
In order to identify the spatial distribution characteristics of DVE and AVE during development, the authors combined newly identified marker molecules, whole embryonic immunofluorescence imaging and published spatial transcriptome mining to find that multiple stages of DVE or AVE populations can be identified and labeled in situ, and have different localization and distribution rules
.
Furthermore, the comparative analysis of gene expression profiles of cell populations between different species showed that unlike mice, only AVE-related populations existed in non-human primates and human embryos, suggesting that there may be large differences in anterior and posterior axis-related populations and specialization patterns in different species
.

In recent years, embryo-like systems based on stem cell pluripotency and self-assembly have brought new ideas
to the study of human embryos.
On the other hand, embryo-like embryos present a certain degree of postimplantation development bottleneck in in vitro culture, and anteroposterior axis formation is the prerequisite
for the normal development of embryos around the bedside stage.
To see if there was a cell population with anteroposterior axis specialization potential in the embryos, the authors conducted further comparative analysis and found that, unlike natural blastocysts in humans, current human blastoids constructed from stem cells do not contain DVE or AVE precursor cells
.
This result suggests that focusing on and adding key precursor cells with anteroposterior axis potential in the process and system of induction embryos may be a potential strategy
to optimize embryo-like systems and enhance postimplantation development potential.

Combined with spatiotemporal transcriptomics and in situ spatial distribution verification, the anterior and posterior axis occurrence of mammals was analyzed from multiple angles

In summary, this study defines the whole process of development of key populations DVE and AVE during the anteroposterior axis of embryonic axis in the gene expression dimension: these two groups of cells are likely to originate in the blastocyst stage before implantation, and then specialize along their independent developmental pathways, and go through multiple representative stages
respectively.
Compared to mice, primate embryos contain only AVE, and existing mouse and human embryo models lack DVE or/or AVE-related lineages
.
This study reveals the origin and specialization of key lineages during the formation of anteroposterior axes in mammalian embryos, and provides clues and basis
for in-depth understanding of the development and molecular regulation patterns of embryonic perinatal embryos.

Assistant Professor Zhou Fan, School of Life Sciences, Tsinghua University, is the corresponding author
of this paper.
Zhu Qingyuan, research assistant of Zhou Fan's research group at the School of Life Sciences of Tsinghua University, Ge Jitao, a 2020 doctoral student, and Liu Ying, a 2021 doctoral student, are joint first authors, along with postdoctoral fellow Xu Jiawen and 2020 doctoral student Yan Shengyi
.
The Laboratory Animal Center of Tsinghua University, the State Key Laboratory of Membrane Biology Platform, and the Nikon Imaging Center of Tsinghua University provided equipment or technical support
for this research.