The Lacrimal Gland: A One-Dimensional Model for Budding Morphogenesis To Generate a Glandular Structure
The lacrimal gland is a tear-secreting organ which lubricates and protects the ocular surface. Because the initial budding and elongation of the lacrimal gland primordia occurs along a straight line, it serves as a one-dimensional model for studying the mechanisms of FGF signaling. Among 22 FGF ligands and 4 FGF receptors, only the Fgf10-Fgfr2 pair is both necessary and sufficient for the induction of development in the lacrimal gland. We are studying the accumulative effect of ligand, receptor, cytoplasmic and transcriptional factors effectors to understand the remarkable specificity of FGF10/Fgf10 signaling in lacrimal gland development.
The Lens: A Two-Dimensional Model for Patterning and Differentiation of a Sensory Organ
Based on the rotational symmetry of the anterior-posterior axis, the lens can be depicted in a two-dimensional space. This relative structural simplicity presents an entry point to study the complexity of cell signaling. With a limited collection of communication channels, biological systems often reuse signaling pathways like FGF for diverse functions. The challenge is how to convey different message via the same signal. we are exploring how repetitive uses of FGF signaling guide consecutive phases of lens development. Although FGF signaling has been most extensively studied for its role in cell proliferation and differentiation, our recent research has also indicated that FGF signaling regulates cell adhesion. The lens thus provides an excellent venue to study cross talk between growth factor signaling and mechanobiology.
The Retina: A Three-Dimensional Model for Neurogenesis and Homeostasis in the Central Nervous System
The diversity of FGF signaling is exemplified in the retina, where FGF’s influence not only affects developmental patterning and fate determination, but homeostasis and metabolism. We demonstrate that the vertebrate eye cup is specified in a phase transition mode that can be programed reversibly by a binary code of FGF and Wnt signaling. Our single-cell and lineage tracing analysis further reveal that FGF signaling controls the stem cell–like property of self-renewal, differentiation, and survival in optic cup progenitors. In adult retina, we are investigating the role of FGF signaling in protecting photoreceptors from degeneration and in promoting Müller cells to regenerate retinal neurons.
The Neural-Glial-Endothelial Complex
During eye development, the vasculature invades the neonatal retina along the preexistent scaffold of astrocytes, which also secrete angiogenic factors to promote migration of endothelial cells. We find that ablation of glycosaminoglycan (GAG) side chains of proteoglycans in the neuroretina disrupts the retinal basement membrane, leading to arrested astrocyte migration and reduced angiogenesis. Using genetic deletion and time-lapse imaging, we show that retinal astrocytes require neuronal-derived PDGF as a chemoattractive cue and the retinal basement membrane as a migratory substrate. Our long-term goal is to understand the signaling mechanism mediating the neural-glial-endothelial interaction, which underlies a cohort of blinding diseases such as retinopathy of prematurity (ROP), coloboma, and glaucoma.