They reveal a key bridge in the genetic communication of craniofacial development

A recent study has identified an essential genetic mechanism that regulates the formation and migration of cranial neural crest cells, essential for the development of facial structure. This finding expands knowledge of the roles that certain genes play in a critical step that occurs in embryonic development, and opens the door to a greater understanding of the genetic causes behind certain congenital diseases.

The study was carried out by an international team made up of, among others, Samantha M. Barnada, from Thomas Jefferson University in Philadelphia, United States; by Eloísa Herrera, who directs the Generation and Regeneration of Bilateral Circuits laboratory at the Institute of Neurosciences (IN), a joint center of the Higher Council for Scientific Research (CSIC) and the Miguel Hernández University (UMH) of Elche, in Spain; and by Marco Trizzino, whose laboratory at Imperial College London (United Kingdom) is an expert in the study of human stem cells.

The authors of the study have revealed how the ZIC2 gene, 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 facial structures.

The team conducted experiments with stem cells derived from patients with Coffin-Siris syndrome (CSS), a rare genetic disorder that occurs when there is insufficiency in the function of these genes and is characterized by abnormalities in various parts of the body, including problems in the extremities, intellectual delay and craniofacial malformations. These cells were used to study how genetic alterations in ARID1A affect EMT genetic programs and ZIC2 gene function. The analyzes included advanced techniques such as RNA-seq and ChIP-seq, which allowed the identification of genes regulated by this molecular axis.

In addition, the team used animal models, such as mice and chick 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. “This is how we discovered that ZIC2 is expressed in the premigratory cells of the neural crest, just before they begin their movement,” says Herrera.

Possible treatments in 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 properly, ZIC2 cannot occupy the genomic sites necessary to activate EMT genes, which interferes with neural crest migration, triggering aberrant cell trajectories and causing craniofacial defects.

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

This research sheds light on the genetic mechanisms underlying 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.

The study is titled “ARID1A-BAF coordinates ZIC2 genomic occupancy for epithelial-to-mesenchymal transition in cranial neural crest specification.” And it has been published in the academic journal The American Journal of Human Genetics. (Source: Elena Garrido / IN / CSIC)