Cleft palate is among the most common birth defects in humans. In recent years, significant progress has been achieved in identifying genetic factors associated with cleft palate in humans. In addition, targeted mutagenesis studies in mice have found that mutations in a large number of genes each could cause cleft palate. However, little is known about how these genes are connected to form the molecular network controlling palate development. Recent advances in massively parallel sequencing technologies, in combination with chromatin immunoprecipitation (ChIP-seq) and gene expression profiling approaches, have enabled comprehensive analyses of genome-wide transcriptional regulation of gene expression in development and disease processes. In this proposal, we focus on characterizing the roles of two critical transcription factors, Osr2 and Pax9, in palate development. Mice lacking either Osr2 or Pax9 have complete cleft palate. Expression of both Osr2 and Pax9 mRNAs in the palatal mesenchyme is positively regulated by Fgf signaling. In addition, previous studies suggested that both Bmp and Fgf signaling pathways play critical roles in palate development and that Bmp signaling appeared to repress Pax9 gene expression in the anterior region of the developing palate. We propose three specific aims for this research project: (1) to characterize the roles of and the molecular pathway involving Osr2 in palate development using ChIP-seq and genome-scale gene expression profiling approaches in combination with mutant mouse studies;(2) to characterize the roles of and molecular pathway involving Pax9 in palate development and to investigate whether Osr2 and Pax9 interact directly and/or converge on regulation of downstream genes during palate development;and (3) to investigate the roles of the Bmp and Fgf signaling in molecular patterning of the secondary palate and whether Osr2 and Pax9 play critical roles in the integration of these signaling pathways in the regulation of palate development. These studies will not only significantly improve our understanding of the essential roles of Osr2 and Pax9 in palate development but also provide valuable resources and a transcriptional regulatory framework for comprehensive elucidation of the gene regulatory network controlling palate development.
Cleft palate is among the most common birth defects. Cleft palate occurs due to gene mutations and/or environmental perturbations disrupting palate development during pregnancy. This research project aims to understand the mechanisms controlling palate development and how mutations cause cleft palate. Information gained from our studies will ultimately lead to development of methods for prevention and/or more effective treatment of cleft palate.
|Li, C; Lan, Y; Krumlauf, R et al. (2017) Modulating Wnt Signaling Rescues Palate Morphogenesis in Pax9 Mutant Mice. J Dent Res 96:1273-1281|
|Fu, X; Xu, J; Chaturvedi, P et al. (2017) Identification of Osr2 Transcriptional Target Genes in Palate Development. J Dent Res 96:1451-1458|
|Li, C; Lan, Y; Jiang, R (2017) Molecular and Cellular Mechanisms of Palate Development. J Dent Res 96:1184-1191|
|Lan, Yu; Zhang, Nian; Liu, Han et al. (2016) Golgb1 regulates protein glycosylation and is crucial for mammalian palate development. Development 143:2344-55|
|Xu, Jingyue; Liu, Han; Lan, Yu et al. (2016) A Shh-Foxf-Fgf18-Shh Molecular Circuit Regulating Palate Development. PLoS Genet 12:e1005769|
|Xu, Jingyue; Liu, Han; Chai, Ok Hee et al. (2016) Osr1 Interacts Synergistically with Wt1 to Regulate Kidney Organogenesis. PLoS One 11:e0159597|
|Liu, Han; Xu, Jingyue; Liu, Chia-Feng et al. (2015) Whole transcriptome expression profiling of mouse limb tendon development by using RNA-seq. J Orthop Res 33:840-8|
|Lan, Yu; Xu, Jingyue; Jiang, Rulang (2015) Cellular and Molecular Mechanisms of Palatogenesis. Curr Top Dev Biol 115:59-84|
|Breidenbach, Andrew P; Aschbacher-Smith, Lindsey; Lu, Yinhui et al. (2015) Ablating hedgehog signaling in tenocytes during development impairs biomechanics and matrix organization of the adult murine patellar tendon enthesis. J Orthop Res 33:1142-51|
|Kwon, H J E; Park, E K; Jia, S et al. (2015) Deletion of Osr2 Partially Rescues Tooth Development in Runx2 Mutant Mice. J Dent Res 94:1113-9|
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