Craniofrontonasal syndrome (CFNS) is an X-linked disease that affects multiple aspects of craniofacial development and is caused by mutations in the EFNB1 gene. Frontonasal dysplasia is a defining attribute of CFNS, but the developmental etiology underlying ephrin-B1 function in this context is incompletely defined. We propose to utilize the mouse as a model to understand the basic developmental mechanisms by which EFNB1 acts to control development of the midface. CFNS is an unusual disease in that whereas EFNB1 is an X-linked gene, heterozygous females are more severely affected than hemizygous males. This is related to the fact that heterozygous females represent a mosaic of ephrin-B1 expressing and non-expressing cells. Using a combination of mouse genetics and molecular biology approaches, we will define the mechanistic basis for this phenomenon. Finally, we propose a possible general strategy for preventing CFNS, whose feasibility we will begin to test in a mouse model.

Public Health Relevance

Craniofrontonasal syndrome (CFNS) is an X-linked disease that affects multiple aspects of craniofacial development and is caused by mutations in the EFNB1 gene. This proposal seeks to define the developmental mechanisms underlying CFNS and begin to examine a strategy for therapeutic intervention. This work should provide insight into the developmental functions of EFNB1, and directions for designing preventative or therapeutic strategies for a human birth defect.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE023337-05
Application #
9265829
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Scholnick, Steven
Project Start
2013-07-09
Project End
2018-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
5
Fiscal Year
2017
Total Cost
$396,250
Indirect Cost
$146,250
Name
University of California San Francisco
Department
Anatomy/Cell Biology
Type
Schools of Dentistry
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118
Niethamer, Terren K; Bush, Jeffrey O (2018) Getting direction(s): The Eph/ephrin signaling system in cell positioning. Dev Biol :
Kim, Seungil; Prochazka, Jan; Bush, Jeffrey O (2017) Live Imaging of Mouse Secondary Palate Fusion. J Vis Exp :
Niethamer, Terren K; Larson, Andrew R; O'Neill, Audrey K et al. (2017) EPHRIN-B1 Mosaicism Drives Cell Segregation in Craniofrontonasal Syndrome hiPSC-Derived Neuroepithelial Cells. Stem Cell Reports 8:529-537
O'Neill, Audrey K; Kindberg, Abigail A; Niethamer, Terren K et al. (2016) Unidirectional Eph/ephrin signaling creates a cortical actomyosin differential to drive cell segregation. J Cell Biol 215:217-229
Kim, Seungil; Lewis, Ace E; Singh, Vivek et al. (2015) Convergence and extrusion are required for normal fusion of the mammalian secondary palate. PLoS Biol 13:e1002122
Lewis, Ace E; Hwa, Jennifer; Wang, Rong et al. (2015) Neural crest defects in ephrin-B2 mutant mice are non-autonomous and originate from defects in the vasculature. Dev Biol 406:186-95
Goodwin, Alice F; Kim, Rebecca; Bush, Jeffrey O et al. (2015) From Bench to Bedside and Back: Improving Diagnosis and Treatment of Craniofacial Malformations Utilizing Animal Models. Curr Top Dev Biol 115:459-92
Agrawal, Puja; Wang, Michael; Kim, Seungil et al. (2014) Embryonic expression of EphA receptor genes in mice supports their candidacy for involvement in cleft lip and palate. Dev Dyn 243:1470-6