Skull and facial abnormalities are among the most common birth defects, and such defects often hinder the physical and mental development of the affected child. In a normal developing child, skull bones are connected by fibrous joints called sutures, which allow pressure to be released as the brain grows and expands. Craniosynostosis is the premature fusion of these sutures that are present in newborns and infants. Saethre-Chotzen syndrome, a disorder characterized by craniosynostosis and other facial irregularities, has been known for over a decade to be caused by mutations in a gene called TWIST1. In mice and zebrafish, Twist1 functions to delegate certain cells to become ectomesenchyme, which is tissue that will later form the skull and facial bones. When the embryo is developing, mutations in one copy of Twist1 result in craniosynostosis, which is caused by defective maintenance of early tissue progenitors in the suture regions. Recently, our collaborator has identified mutations in a related gene, TCF12, in a subset of individuals who present with Saethre-Chotzen syndrome but do not carry TWIST1 mutations. Tcf12 encodes a protein that belongs to a class (class I bHLH) that is known to bind to another class of proteins (class II bHLH), which Twist1 belongs. We propose that Tcf12 and Twist1 function together as one to instruct cells in becoming ectomesenchyme and maintain sutures. In support of this, both tcf12 and twist1 genes in zebrafish are expressed during the time the ectomesenchyme is forming. Also shown in mice, mutations in one copy of each Tcf12 and Twist1 result in complete fusion of a particular set of sutures. Mutations in one copy of Twist1 alone result in only partial premature suture fusion in mice. Here, I use strengths of both zebrafish and mouse models to investigate potential functions of Tcf12-Twist1 molecules in both ectomesenchyme specification and suture maintenance. My findings will better reveal the genetic basis of premature fusion of skull bones in Saethre-Chotzen syndrome.

Public Health Relevance

Skull and facial abnormalities are among the most common birth defects, and such defects often hinder the physical and mental development of the affected child. My findings will better reveal the genetic basis of premature fusion of skull bones in Saethre-Chotzen syndrome, a human birth defect with devastating consequences on skull and brain growth in children.

Agency
National Institute of Health (NIH)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31DE024031-01A1
Application #
8784033
Study Section
NIDR Special Grants Review Committee (DSR)
Program Officer
Frieden, Leslie A
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Southern California
Department
Biochemistry
Type
Schools of Medicine
DUNS #
City
Los Angeles
State
CA
Country
United States
Zip Code
90089