Genetic Regulation of Developmental Clocks
In vitro segmentation clock model — a window to understand developmental timing: To identify the principles governing temporal developmental program, we are currently focused on the dynamic function of the segmentation clock, which controls somitogenesis with a species-specific periodicity. Recently, we established in vitro segmentation clock models using human ESC-derived PSM cells, displaying a human-specific gene oscillatory periodicity recapitulating segmentation clock in vivo. Equipped with these novel systems, we are now poised to make significant insights and ask key questions such as: What controls the tempo of a developmental clock? What are the extrinsic or intrinsic factors that could influence developmental timing? How do cells translate this temporal code into spatial identity information during development?

Stem Cells and Regenerative Medicine
Modeling congenital spinal deformity in a dish — a model to search for novel therapeutic solutions: Defects in segmentation result in congenital vertebral anomalies, which are estimated to affect approximately 1 in 1000 live births. Those conditions include: 1) spondylocostal dysostosis (SCDO), a severe but rare condition with misshaped or fused vertebrae, and 2) congenital scoliosis (CS), a prevalent but less severe condition with lateral curvature of the spine. In both conditions, mutations have been identified primarily in the conserved NOTCH signaling pathway. However, due to the lack of proper human cell models, little is known about how these mutations or any additional environmental factors (e.g., temperature, hypoxia) disrupt the process of segmentation. To meet this need, we used genome editing to establish an in vitro model of SCDO4 in which human ESCs harbor the exact missense point mutation in exon 2 of HES7 (OMIM:608059), resulting in an Arg-to-Trp (R25W) substitution at an evolutionarily conserved residue in the DNA-binding domain (HES7R25W). We will use our models to: 1) serve as a cell-based platform for screening novel regulators to restore normal gene oscillation and 2) effectively build additional SCDO/CS models to investigate the influence of environmental factors on the penetrance of CS etiology.

Biology of species-specific pluripotent stem cells
Species-specific cellular reprogramming — an opportunity to compare species-specific pluripotency and functional derivatives: We are interested in developing iPSCs from mammalian species with various gestation length for comparative developmental biology. Because the signaling requirement for maintaining the pluripotent state could be species-specific, standard mouse or human PSC protocols may not support other species directly. This presents both challenges and opportunities to explore the evolutionary conserved and unique features of pluripotency and cellular reprogramming.