Here we report our study on one of the skeletal diseases, the Apert syndrome, which occurs at one in 65,000 live births in human. We first introduced a Ser252Trp mutation that is found in human Apert patients, to mouse FGFR2 gene. The FGFR2-Ser252Trp mutant mice displayed phenotypes mimicking the human Apert disease. We then use this mouse model to test preventivetherapeutic approaches to see if the disease can be prevented or cured. We show that a small hairpin RNA (shRNA), targeting the FGFR2-S252W mutant form mRNA in this mouse model, completely inhibits Apert-like craniosynostosis and the related defects. We further show that restoration of normal FGFR2 signaling is manifested by an alteration of ERK12 activity, implicating ERK and its downstream genes in disease expressivity. Furthermore, treatment of mutant mice with an ERK inhibitor results in a complete cure of mutant phenotypes. These results illustrate an unknown pathogenic role of ERK activation in the FGFR2-S252W-associated craniosynostosis and represent a new concept of shRNA-mediated therapy for diseases caused by gain of functions associated with activating point mutations in human genome.

Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Zip Code
Lee, M-H; Lahusen, T; Wang, R-H et al. (2012) Yin Yang 1 positively regulates BRCA1 and inhibits mammary cancer formation. Oncogene 31:116-27
Zhu, Min; Yi, Ming; Kim, Chang Hee et al. (2011) Integrated miRNA and mRNA expression profiling of mouse mammary tumor models identifies miRNA signatures associated with mammary tumor lineage. Genome Biol 12:R77
Choksi, Swati; Lin, Yong; Pobezinskaya, Yelena et al. (2011) A HIF-1 target, ATIA, protects cells from apoptosis by modulating the mitochondrial thioredoxin, TRX2. Mol Cell 42:597-609
Sato, Yukiyasu; Heimeier, Rachel A; Li, Cuiling et al. (2011) Extracellular domain of CD98hc is required for early murine development. Cell Biosci 1:7
Hsiao, Yi-Hsuan; Deng, Chuxia; Mason, Jeffrey T et al. (2011) Hidden malignant cells within leukocyte aggregates: seeds for invasive and metastatic cancer? Cancer Epidemiol 35:475-9
Jeon, Jongrye; Dencker, Ditte; Wörtwein, Gitta et al. (2010) A subpopulation of neuronal M4 muscarinic acetylcholine receptors plays a critical role in modulating dopamine-dependent behaviors. J Neurosci 30:2396-405
Fishler, T; Li, Y-Y; Wang, R-H et al. (2010) Genetic instability and mammary tumor formation in mice carrying mammary-specific disruption of Chk1 and p53. Oncogene 29:4007-17
Liu, Ying; Kawai, Kirio; Khashabi, Shabnam et al. (2010) Inactivation of Smad4 leads to impaired ocular development and cataract formation. Biochem Biophys Res Commun 400:476-82
Xiao, Cuiying; Kim, Hyun-Seok; Lahusen, Tyler et al. (2010) SIRT6 deficiency results in severe hypoglycemia by enhancing both basal and insulin-stimulated glucose uptake in mice. J Biol Chem 285:36776-84
Bunting, Samuel F; Callén, Elsa; Wong, Nancy et al. (2010) 53BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks. Cell 141:243-54

Showing the most recent 10 out of 20 publications