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How Genes Affect Facial Development

Zebrafish studies can yield insight into human development.

DiGeorge syndrome (also called 22q11.2 deletion syndrome, among other names) affects an estimated 1 in 4,000 people. Children with DiGeorge syndrome often have facial defects that include an undeveloped chin, heavy eyelids, and ears that are rotated back. Other common signs and symptoms include heart defects and recurrent infections caused by problems with the immune system.

Structures within the head and neck develop from embryonic features called pharyngeal pouches. These emerge from the endoderm, the inner layer of the embryo. DiGeorge defects are thought to be at least partly due to malformation of these pouches. However, the details of these developmental steps remain poorly understood.

To understand how genes cause complex developmental problems, researchers often use model systems, such as fish, worms, and mice. DiGeorge syndrome has been associated with deletion of a region of chromosome 22, which contains the TBX1 gene. Zebrafish with Tbx1 mutations have severe defects in pouch formation and facial skeletal development. Similarly, Tbx1 mutant mice lack pouches and have defects that mimic those of people with DiGeorge syndrome.

Drs. Chong Pyo Choe and J. Gage Crump at the University of Southern California used zebrafish to investigate how Tbx1 might control craniofacial formation. Their study was supported in part by NIH’s National Institute of Dental and Craniofacial Research (NIDCR). Results were published in the September 2014 issue of Development.

In previous work, the team found that the genes fgf8a and wnt11r are expressed in the mesoderm, the middle layer of the embryo, when pouches begin to form. Both genes are required for pouch development. In this study, the researchers showed that Tbx1 is required for the expression of both genes in the developing mesoderm. Restoring fgf8a and wnt11r expression in the mesoderm bypasses mutant tbx and rescues its effects on pouch development.

Using advanced time-lapse imaging techniques to track individual cells, the scientists showed that pouch-forming epithelial cells from the endoderm migrate toward areas expressing fgf8a in adjacent mesoderm. Wnt11r enables these cells to respond to Fgf8a and begin the process of forming pouches.

This research showed that Tbx1, acting through fgf8a and wnt11r, functions in the facial mesoderm to coordinate multiple steps in pouch formation. “Whereas it has been recognized that mutations in TBX1 underlie DiGeorge syndrome in patients, our study reveals how this master control gene works to organize the complex cellular rearrangements that build the face,” Crump says.

Defects in pouch development underlie several human birth defects. Continuing studies in model systems such as zebrafish will help us understand the signaling pathways involved and yield critical insights into the origins of many congenital disorders.

—by Harrison Wein, Ph.D.