Title Genetic Regulatory Network in Craniofacial Development Abstract This proposal continues our efforts to decipher the skeletogenic signaling network underlying craniofacial development and disease. The craniofacial skeleton consists of viscerocranium and neurocranium, which is subdivided into the calvarium and chondrocranium. During development of the calvarium, cranial sutures serve as the growth center for skeletogenesis. Defects in suture morphogenesis resulting in premature closure cause craniosynostosis, a devastating childhood disease affecting 1 in ~2,500 individuals. Although human genetic analyses have identified genes associated with the pathogenesis, little is known about the regulation of suture closure essential for development of a healthy skull. In the previously proposed investigation, we have elucidated the mechanisms by which Axin2 regulates suture morphogenesis through modulations of Wnt and downstream signaling pathways. The crosstalk of BMP and FGF signaling plays a pivotal role in Wnt-mediated craniofacial bone development. Furthermore, skeletal stem cells residing in the suture mesenchyme have been successfully identified and isolated in our laboratory. This suture stem cell (SuSC) population is responsible for calvarial development in infants as well as homeostatic maintenance in adults. Upon injury, the dormant SuSCs respond quickly and contribute directly to bone repair in a cell autonomous fashion. In vivo clonal analysis demonstrates calvarial bone regeneration at a single cell level. Implantation of SuSCs to an injured site shows not only long-term survival but also facilitation of bone healing via direct engraftments in which the implanted stem cells give rise to osteogenic cell types in replacement of the damaged tissue. The newly discovered SuSCs thus provides an outstanding opportunity to gain novel insights into etiology of craniosynostosis. In this proposal, we continue our in-depth evaluations of SuSCs by examining their regulation essential for healthy development and homeostasis of the calvarium. We will concentrate on elucidation of molecular and cellular mechanisms underlying craniosynostosis caused by dysregulation of SuSCs.

Public Health Relevance

This proposal investigates basic genetic elements controlling the formation of a healthy skull during craniofacial skeletogenesis. Using genetically modified mouse strains, we elucidate the mechanism underlying skeletal stem cell-mediated calvarial bone development and disease. The results obtained are highly relevant to the health of human development in craniofacial deformities, e.g. craniosynostosis and cleiocranial dysplasia, and has potentials to gain insights into therapeutic strategies for human diseases.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Lumelsky, Nadya L
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University of Rochester
School of Medicine & Dentistry
United States
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Shen, Chengyong; Li, Lei; Zhao, Kai et al. (2018) Motoneuron Wnts regulate neuromuscular junction development. Elife 7:
Maruyama, Takamitsu; Jiang, Ming; Abbott, Alycia et al. (2017) Rap1b Is an Effector of Axin2 Regulating Crosstalk of Signaling Pathways During Skeletal Development. J Bone Miner Res 32:1816-1828
Maruyama, Eri O; Lin, Heng; Chiu, Shang-Yi et al. (2016) Extraembryonic but not embryonic SUMO-specific protease 2 is required for heart development. Sci Rep 6:20999
Maruyama, Takamitsu; Jeong, Jaeim; Sheu, Tzong-Jen et al. (2016) Stem cells of the suture mesenchyme in craniofacial bone development, repair and regeneration. Nat Commun 7:10526
Zhu, Xiao-Jing; Liu, Yudong; Yuan, Xueyan et al. (2016) Ectodermal Wnt controls nasal pit morphogenesis through modulation of the BMP/FGF/JNK signaling axis. Dev Dyn 245:414-26
Das, Soumyashree; Yu, Shiyan; Sakamori, Ryotaro et al. (2015) Rab8a vesicles regulate Wnt ligand delivery and Paneth cell maturation at the intestinal stem cell niche. Development 142:2147-62
McGee-Lawrence, Meghan E; Carpio, Lomeli R; Bradley, Elizabeth W et al. (2014) Runx2 is required for early stages of endochondral bone formation but delays final stages of bone repair in Axin2-deficient mice. Bone 66:277-86
Li, T-F; Yukata, K; Yin, G et al. (2014) BMP-2 induces ATF4 phosphorylation in chondrocytes through a COX-2/PGE2 dependent signaling pathway. Osteoarthritis Cartilage 22:481-9
Sakamori, Ryotaro; Yu, Shiyan; Zhang, Xiao et al. (2014) CDC42 inhibition suppresses progression of incipient intestinal tumors. Cancer Res 74:5480-92
Zhu, Xiao-Jing; Liu, YuDong; Dai, Zhong-Min et al. (2014) BMP-FGF signaling axis mediates Wnt-induced epidermal stratification in developing mammalian skin. PLoS Genet 10:e1004687

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