The U.S. journal Developmental Cell published a Chinese research article titled "Single-cell Analysis of Human Retina Identifies Evolutionarily Conserved and Species-specific Mechanisms Controlling Development" on its website on May 7, 2020. During their scientific studies, researchers performed high-throughput sequencing of single cells in 16 stages of human retinal development and four different maturation stages of retinal organoid to construct a transcriptome dataset of the development of the human retina and explain the molecular controlling mechanism of cell-type fate specification and the formation of macula lutea in retinal growth. In addition, they also conducted cross-species analyses to uncover evolutionary conservation and species-specific patterns shown in the retinal development of both human beings and mice.

Visual sense is an important channel for human beings to get information. Optical signals can be converted to electric signals via the human retina located in the back of the eyeball and the signals delivered to the brain via the optic nerve. As the macula lutea, a small yellowish area of the retina specific to primate species, is responsible for photopic vision and color sense, any pathological changes to it will lead to noticeable visual impairment. Therefore, to learn more about the formation of cells in the human retina and its molecular mechanism in the process of development, studying the developmental features of the macula lutea is of great importance for the treatment of congenital retinal diseases.

Researchers employed high-throughput single-cell transcriptome technology to conduct sequencing analyses of 118,555 single cells from retinal organoid, human embryos and adulthood at 20 time points and categorized them into 126 cellular subtypes. They divided these cellular subtypes into 11 populations with marker genes, depicted the developmental trajectory of the retina, and found sequences and specific times of the occurrence of major retinal cells through making analyses of the formation of cellular types in different developmental stages. To further explore gene expression regulatory network of retinal cells, they performed pseudotime analyses of all cellular types and relevant retinal cells, and discovered controlling genes of cell-type fate specification.

Moreover, researchers collected samples of 20-week-old human embryos, macula lutea and peripheral areas from infants eight days after their birth to study developmental specification of macula lutea. Drawing upon the analyses of regionally differentiated genes, they found 10 genes connected with the formation of macula lutea. For instance, a gene coded CYP26A1 can dilute the concentration of retinoic acid, which will in turn lead to the formation of macula lutea. An ISH (In Situ Hybridization) experiment showed that the CYP26A1 gene is a specific expression of retinal progenitors and muller cells in the macula lutea. Another gene coded CTGF is a downstream target gene of the Hippo-signaling pathway and a specific expression of muller cells in macula lutea. Although more efforts should be made to study the specific function of the Hippo pathway in the early developmental stage of macula lutea, these findings have shown that both retinal cells and muller cells, expressed specifically in the macula lutea, are of great importance to its formation.

Gene controlling networks and spatial expression model of cell-fate specification in retinal cells

This research program has been jointly accomplished by the research team of Professor Wang Xiaoqun from the Institute of Biophysics at the Chinese Academy of Sciences (CAS), the team of Professor Xue Tian at the University of Science and Technology of China (USTC), and many research institutes at home and abroad. Together with Wang and Xue, Seth Blacksha, Brian Clark and Rod Bremner are co-corresponding authors of the article. Its co-first authors include Lu Yufeng, a doctoral student with the CAS Institute of Biophysics, Yi Wenyang, a doctoral student with the USTC, and Fion Shiau. Major contributors also include He Sheng, Zhuo Yan and Zuo Zhentao, who are research fellows with the CAS Institute of Biophysics. The research program has received financial assistance from the National Key R&D Program of China affiliated to the Ministry of Science and Technology and the National Natural Science Foundation.

The web link for this paper is https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3000705

(Reported by Dr. WANG Xiaoqun's group)