The aim of my laboratory is to understand the cellular and molecular mechanisms in craniofacial birth defects and diseases such as cleft palate and xerostomia. Specifically, we are working to characterize the cell signaling network and dynamic system of protein turnover that directs craniofacial disorders, using multidisciplinary approaches including mouse genetics, genomics, proteomics, biochemistry, and molecular biology. The following research projects are ongoing in my laboratory.
Role of cellular metabolism during development and diseases
Cellular metabolic aberrations result in craniofacial deformities in humans and mice. Interestingly, mice with cholesterol synthesis deficiency have severe malformations specifically in the craniofacial region while the rest of their body is largely unaffected. The majority of cells in the craniofacial region are derived from cranial neural crest (CNC) cells, which is a multi-potent cell population that gives rise to a variety of different cell types. These results suggest that CNC cells are more sensitive to metabolic aberrations than those of other regions during embryogenesis. However, it is still unknown how molecules related to cellular metabolism are regulated during craniofacial development. In addition, the possible relationship between cellular metabolism and the observed craniofacial deformities remains unclear. Our aim is to identify gene mutations and protein modifications related to craniofacial disorders and provide the basis for tests aimed at identifying higher-risk persons.
Role of autophagic machinery in development and diseases
Autophagy is an evolutionarily conserved bulk-protein degradation system, in which isolation membranes engulf cytoplasmic constituents and the resulting autophagosomes transport them to lysosomes. This process is crucial for the removal and breakdown of cellular components such as damaged proteins and aged organelles. Autophagic activity is altered in various diseases and birth defects in humans and mice. An understanding of the manner in which autophagy is regulated is critical for understanding normal craniofacial development as well as congenital malformations. Our aim is to identify the molecular regulatory mechanism of autophagic machinery related to developmental defects and diseases.
1. Iwata J, Suzuki A, Yokota T, Ho TV, Pelikan RC, Urata M, Sanchez-Lara P, and Chai Y. TGFâ regulates epithelial–mesenchymal interactions via WNT signaling activity to control muscle development in the soft palate. Development (Under revision)
2. Iwata J, Suzuki A, Pelikan RC, Ho TV, and Chai Y. (2013) Cranial neural crest cells regulate tongue muscle formation via TGFâ–mediated BMP and FGF signaling. J. Biol. Chem. (in press) This manuscript has been selected as a Journal of Biological Chemistry “Papers of the Week”.
3. Iwata J, Suzuki A, Pelikan RC, Sanchez-Lara PA, and Chai Y. (2013) Modulation of lipid metabolic defects rescues cleft palate in Tgfbr2 mutant mice. Hum. Mol. Genetics (in press)
4. Song Z*, Liu C*, Iwata J*, Gu S, Suzuki A, Sun C, He W, Shu R, Li L, Chai Y, and Chen Y. (2013) Mice with Tak1 deficiency in neural crest lineage exhibit cleft palate associated with abnormal tongue development. J. Biol. Chem., Apr 12; 288 (15): 10440-50. (*These authors contributed equally to this work.)
5. Iwata J, Suzuki A, Deng X, Pelikan RC, Ho TV, Sanchez-Lara PA, Yokota T, Urata M, and Chai Y. (2013) Smad4-Irf6 genetic interaction and TGFâ–mediated IRF6 signaling cascade are crucial for palatal fusion in mice. Development, Mar; 140 (6): 1220-30.
6. Pelikan RC*, Iwata J*, Suzuki A, Chai Y, and Hacia JG. (2013) Identification of candidate downstream targets of TGFâ signaling during palate development by genome-wide transcript profiling. J. Cell Biochem., Apr; 114 (4): 796-807. (*These two authors contributed equally to this work.)
7. Iwata J, Hacia JG, Suzuki A, Sanchez-Lara PA, Urata M, and Chai Y. (2012) Modulation of non-canonical TGF-â signaling prevents cleft palate in Tgfbr2 mutant mice. J. Clin. Invest., Mar 1; 122 (3): 873-85.
8. Iwata J, Tung L, Urata M, Hacia JG, Pelikan RC, Suzuki A, Ramenzoni L, Chaudhry O, Parada C, Sanchez-Lara PA, and Chai Y. (2012) Fibroblast growth factor 9 (FGF9)–pituitary homeobox 2 (PITX2) pathway mediates transforming growth factor beta (TGFâ) signaling to regulate cell proliferation in palatal mesenchyme during mouse palatogenesis. J. Biol. Chem., Jan 20; 287 (4): 2353-63.
9. Iwata J, Parada C, and Chai Y. (2011) The mechanism of TGF-â signaling during palate formation: a novel target for prevention of cleft palate. Oral Diseases, Nov; 17 (8): 733-744.
10. Iwata J, Hosokawa R, Sanchez-Lara PA, Urata M, Slavkin H, and Chai Y. (2010) Transforming growth factor-beta regulates basal transcriptional regulatory machinery to control cell proliferation and differentiation in cranial neural crest–derived osteoprogenitor cells. J. Biol. Chem., Feb 12; 285 (7): 4975-82.
11. Sou Y*, Waguri S*, Iwata J*, Ueno T, Fujimura T, Hara T, Sawada N, Yamada A, Mizushima N, Uchiyama Y, Kominami E, Tanaka K, Komatsu M. (2008). The Atg8 conjugation system is indispensable for proper development of autophagic isolation membranes in mice. Mol. Biol. Cell, 19 (11); 4762-75. (*These three authors contributed equally to this work.)
12. Komatsu M, Waguri S, Koike M, Sou Y, Ueno T, Hara T, Mizushima N, Iwata J, Ezaki J, Murata S, Hamazaki J, Nishito Y, Iemura S, Natsume T, Yanagawa T, Uwayama J, Warabi E, Yoshida H, Ishii T, Kobayashi A, Yamamoto M, Yue Z, Uchiyama Y, Kominami E, and Tanaka K. (2007). Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Cell, 131, 1149-1163.
13. Komatsu M, Waguri S, Chiba T, Murata S, Iwata J, Tanida I, Ueno T, Koike M, Uchiyama Y, Kominami E, and Tanaka K. (2006). Loss of autophagy in the central nervous system causes neurodegeneration. Nature, 441 (7095), 880-884.
14. Iwata J, Ezaki J, Komatsu M, Yokota S, Ueno T, Tanida I, Chiba T, Tanaka K, and Kominami E. (2006) Excess peroxisomes are degraded by autophagic machinery in mammals. J. Biol. Chem., 281, 4035-41.