Fibroblast growth factor (Fgf) signaling is important for cell proliferation, migration and differentiation during embryonic development and adult life. Target cells respond in a dose-dependent manner to secreted Fgf ligands. Secreted Fgf ligands form a gradient as they diffuse from a local source through adjacent tissues and interact with the extracellular matrix (ECM). It is largely unclear which ECM components interact with Fgf and how they can shape the Fgf gradient and affect Fgf binding to their receptors. To address these questions, we study how Fgf signaling induces the differentiation of sensory organs in the migrating lateral line primordium in zebrafish. The primordium front cells express the ligands Fgf3 and Fgf10 and the rear cells express the Fgf receptor 1. Fgf signaling induces the rear cells in the primordium to assemble into rosettes, separate from the primordium and differentiate into sensory organs called neuromasts that detect water flow. The primordium deposits a total of 5 to 7 neuromasts during its migration. This model with its optical and genetic accessibility allows us to directly visualize GFP-tagged Fgf ligands and its interactions upon perturbation of ECM components in the live animal. We will use this system to study the interactions between Fgf ligands and two ECM components.
In Aim 1, we will ask how the ECM protein KAL1 regulates the Fgf ligand distribution and signaling. KAL1 is mutated in human patients with Kallmann Syndrome. Patients with impaired KAL1 function lack a sense of smell and fail to develop during puberty due to olfactory axon guidance and gonadotropin releasing hormone neuron migration defects. These defects have been ascribed to KAL1's role as a regulator of Fgf signaling. We will test whether KAL1 binds and sequesters Fgf ligands or facilitates the diffusion of Fgf ligands to modulate the Fgf-signaling range.
In Aim 2, we will ask how sulfation of heparan sufate proteoglycans (HSPGs) by sulfotransferases regulates the distribution and signaling of Fgf ligands. HSPGs are composed of a core protein to which long glycosaminoglycan heparan sulfate (HS) chains are attached. During HSPG synthesis, enzymes modify the disaccharides in the HS chains by - among other things - adding sulfate groups. It is likely that different degrees and patterns of HSPG sulfation alter the sequestration, storage and stability of Fgf ligands in the extracellular space and affect the binding of Fgf ligands to their receptors. We will test these ideas by asking how HSPG sulfation affects the signaling range and distribution of Fgf ligands. These key insights into the biology of Fgf signaling will advance the understanding of biological and medical problems such as defects in embryogenesis and organogenesis and cancer metastasis.
The development of sensory organs such as the ear requires the exact control of potent differentiation cues. We are using a group of cells that differentiates into hair cells in zebrafish as a model to understand how the activity of differentiation cues is controlled. These studies will provide a quantitative understanding of differentiation cues and induction of hair cells, which will inform us how to address medical problems such as hearing defects.
| Wang, John; Yin, Yandong; Lau, Stephanie et al. (2018) Anosmin1 Shuttles Fgf to Facilitate Its Diffusion, Increase Its Local Concentration, and Induce Sensory Organs. Dev Cell 46:751-766.e12 |
