Key bridge revealed in genetic communication of craniofacial development

A study co-led by the Alicante Institute of Neurosciences has discovered the genes that control cell migration, which is the basis for the development of facial structure. The work opens the way to a better understanding of the genetic causes behind certain congenital diseases.

An international team co-led by the Alicante Institute of Neurosciences (IN), a joint centre of the CSIC and the Miguel Hernández University (UMH) in Elche, has identified an essential genetic mechanism that regulates the formation and migration of cranial neural crest cells, which are essential for the development of facial structure.

This finding, published in the journal The American Journal of Human Genetics, expands knowledge of the roles played by certain genes in a critical step that occurs in embryonic development, and opens avenues to a better understanding of the genetic causes behind certain congenital diseases.

«The ZIC2 gene, together with the ARID1A-BAF complex, is crucial in the epithelial-mesenchymal transition. This process allows cells to change shape and migrate in the embryo to form organs and tissues, including facial structures»

This work, led by the CSIC research professor Eloisa Herrera, who directs the laboratory Generation and regeneration of bilateral circuits at the IN, and for Marco Trizzino, whose laboratory at Imperial College London is an expert in the study of human stem cells, has revealed how the gene ZIC2, in collaboration with the ARID1A-BAF complex, plays a crucial role in a process known as epithelial-mesenchymal transition (EMT). This process allows cells to change shape and migrate to their destinations in the embryo to form organs and tissues, including the facial structures.

Patients with Coffin-Siris syndrome

The team conducted experiments with stem cells derived from patients with Coffin-Siris syndrome (CSS), a rare genetic disorder that occurs when these genes fail to function properly and is characterized by abnormalities in various parts of the body, including limb problems, intellectual disability, and craniofacial malformations.

These cells were used to study how genetic alterations in ARID1A affect the genetic programs of the EMT and the function of the ZIC2 gene. The analyses included advanced techniques such as RNA-seq and ChIP-seq, which allowed the identification of the genes regulated by this molecular axis.

In addition, the team used animal models, such as mice and chicken embryos, to observe in vivo how ZIC2 regulates the migration of neural crest cells and to verify the defects associated with the loss of ARID1A in craniofacial development. “Thus we discovered that ZIC2 is expressed in premigratory neural crest cells, just before they begin their movement,” Herrera points out.

Possible treatments for genetic diseases

The results of the study reveal that ARID1A controls a genetic program essential for EMT and that ZIC2 is one of the most important genes in this process. If ARID1A does not function correctly, ZIC2 cannot occupy the genomic sites necessary to activate EMT genes, which interferes with the neural crest migration, triggering aberrant cellular pathways and causing craniofacial defects.

«Knowing how ZIC2 and ARID1A interact in development gives us a key tool to explore possible treatments for congenital genetic diseases» Eloísa Herrera, leader of the work (Institute of Neurosciences)

This research sheds light on the genetic mechanisms that underlie craniofacial development and also offers important clues for the development of targeted therapies. “Knowing how ZIC2 and ARID1A interact in development gives us a key tool to explore possible treatments for congenital genetic diseases,” concludes Herrera.

This work was made possible by funding from the State Research Agency of the Ministry of Science, Innovation and Universities; the “la Caixa” Foundation; the PROMETEO program of the Generalitat Valenciana; the Severo Ochoa Program for Centers of Excellence; the G. Harold and Leila Y. Mathers Foundation; and the National Institutes of Health of the Department of Health and Human Services of the United States.

Reference: Barnada, SM et all. “lARID1A-BAF coordinates ZIC2 genomic occupancy for epithelial-to-mesenchymal transition in cranial neural crest specification.” The American Journal of Human Genetics (2024)

Main Image: The ZIC2 gene drives the migration of neural crest cells (in green) during early embryonic stages, an essential process for the formation of the nervous system.. / IN (CSIC-UMH)

Source: SINC Agency / CSIC

Rights: Creative Commons