This is a proposal to investigate the role of tissue boundaries in cranial suture development and the pathophysiology of craniosynostosis. More broadly, this proposal focuses on how boundaries control pattern in a complex, multicomponent structure. Our recent results on the mechanism of Saethre-Chotzen syndrome, caused by heterozygous loss of function of Twist1, demonstrated that Twist1 mutant mice have a deficiency in the neural crest-mesoderm boundary at the coronal suture. The boundary normally lies between the mesoderm-derived cells of the prospective suture and the neural crest derived osteogenic cells of the prospective frontal bone. We showed that ephrin-Eph signaling, controlled by Twist1, has a role in the maintenance of this boundary: EphA4 is expressed in a layer of cells ectocranial to the prospective bone, through which osteogenic precursor cells migrate. Reduced dosage of Twist1 and EphA4 results in inappropriate targeting of migratory osteogenic precursor (MOP) cells to the coronal suture. This pathfinding defect, we proposed, is a key cause of craniosynostosis in Twist1 and EphA4 mutants. In work now under submission, we found that the Notch ligand, Jagged1, is expressed in a layer of cells in the coronal suture that demarcate the osteogenic-non-osteogenic boundary. Expression of Jagged1 is markedly reduced in such cells in Twist1 mutants. Moreover, conditional inactivation of Jagged1 in these cells results in synostosis, and to an upregulation of Notch2 and Hes1 in the suture. These results are the basis of our three-part overall hypothesis that Twist1 is at a node a regulatory hierarchy, controlling ephrin-Eph and Jagged1/Notch signaling, that Ephrin-Eph signaling functions primarily in the ectocranial mesenchyme to control MOP cell migration, and that Jagged1 functions in sutural mesoderm in the specification of border cells within the suture. To test this hypothesis, we propose first to determine whether the MOP cell targeting defect is inherent in MOP cells or is a result of a change in the ectocranial layer through which MOP cells migrate or of the sutural mesenchyme that they invade. We will approach this using conditional targeting and an array of Cre mice. Second, we will ask whether preventing the expansion of Notch2 and beta catenin expression in sutural cells mitigates the craniosynostosis phenotype, and whether forcing expression of Notch2 in sutural cells causes synostosis. Finally, we will use gene profiling to test the hypothesis that a change in the identity of cells of the coronal suture is the first event in synostosis, and that it is followed by-and exacerbated by-a defect in the targeting of osteogenic precursor cells.
This is a proposal to study how cranial sutures form and how three genes-Twist1, EphA4 and Jagged1- control the development of specific cells within the sutures. These genes are of special interest because humans with mutations in them have birth defects that affect their skulls. By studying how these genes work, we will learn more about basic processes of skull development as well as how mutations in these genes lead to birth defects. In the long term, this work may help to devise new treatments of such birth defects.
|Ishii, Mamoru; Sun, Jingjing; Ting, Man-Chun et al. (2015) The Development of the Calvarial Bones and Sutures and the Pathophysiology of Craniosynostosis. Curr Top Dev Biol 115:131-56|
|Cheng, Su-Li; Behrmann, Abraham; Shao, Jian-Su et al. (2014) Targeted reduction of vascular Msx1 and Msx2 mitigates arteriosclerotic calcification and aortic stiffness in LDLR-deficient mice fed diabetogenic diets. Diabetes 63:4326-37|
|Sharma, Vikram P; Fenwick, AimÃ©e L; Brockop, Mia S et al. (2013) Mutations in TCF12, encoding a basic helix-loop-helix partner of TWIST1, are a frequent cause of coronal craniosynostosis. Nat Genet 45:304-7|
|Sun, Jingjing; Ishii, Mamoru; Ting, Man-Chun et al. (2013) Foxc1 controls the growth of the murine frontal bone rudiment by direct regulation of a Bmp response threshold of Msx2. Development 140:1034-44|
|Cha, Jeeyeon; Sun, Xiaofei; Bartos, Amanda et al. (2013) A new role for muscle segment homeobox genes in mammalian embryonic diapause. Open Biol 3:130035|
|Ishii, Mamoru; Arias, Athena C; Liu, Liqiong et al. (2012) A stable cranial neural crest cell line from mouse. Stem Cells Dev 21:3069-80|
|Ting, Man-Chun; Liao, Chun-Peng; Yan, Chunli et al. (2012) An enhancer from the 8q24 prostate cancer risk region is sufficient to direct reporter gene expression to a subset of prostate stem-like epithelial cells in transgenic mice. Dis Model Mech 5:366-74|
|Daikoku, Takiko; Cha, Jeeyeon; Sun, Xiaofei et al. (2011) Conditional deletion of Msx homeobox genes in the uterus inhibits blastocyst implantation by altering uterine receptivity. Dev Cell 21:1014-25|
|Roybal, Paul G; Wu, Nancy L; Sun, Jingjing et al. (2010) Inactivation of Msx1 and Msx2 in neural crest reveals an unexpected role in suppressing heterotopic bone formation in the head. Dev Biol 343:28-39|
|Yen, Hai-Yun; Ting, Man-Chun; Maxson, Robert E (2010) Jagged1 functions downstream of Twist1 in the specification of the coronal suture and the formation of a boundary between osteogenic and non-osteogenic cells. Dev Biol 347:258-70|
Showing the most recent 10 out of 14 publications