Monday, April 29, 2024
4/29/2024
Principal Investigator: Schlissel, Gavin Project summary Animal development and physiology require regular communication among cell types embedded in tissues. Cellular communication commonly relies on signaling proteins, which can transit the space between cells and relay information across a wide range of spatial scales from nanometers to meters. Proper control of signaling range is strictly necessary during animal development, and dysregulation of signaling range can result in a spectrum of embryonic lethal conditions or developmental disorders. The patterning gradient formed by a signaling protein reflects the signaling protein’s ability to travel through the extracellular matrix, which is an amalgam of protein, sugar and lipids that organize cells in natural tissues. Although signaling proteins are thought to diffuse from their source to their target, many proteins violate the assumptions of free diffusion and instead show context-dependent differences in their signaling range. For example, Sonic Hedgehog family developmental morphogens form signaling gradients over ~10µm in the testes, ~50µm in the developing neural tube or in adult hair follicles, and ~300µm in developing long bones. Notably, tissues in which Sonic Hedgehog forms longer signaling gradients tend to express Scube family extracellular matrix proteins, and Scube family proteins can dramatically extend Sonic Hedgehog signaling gradients in cell culture. I suspect that tissue-specific differences in signaling range might reflect direct regulation of Sonic Hedgehog’s diffusion rate, and that regulated diffusion of Hedgehog might reflect a broadly used strategy to control the size of signaling gradients in animals. To understand how morphogens and the extracellular matrix interact to generate appropriately sized signaling gradients, I will measure variation in protein diffusion both between diverse signaling proteins, and between distinct extracellular environments. I will apply this mechanistic understanding to discover how biochemical features of signaling proteins and the extracellular matrix result in size variation among signaling gradients as well as morphological variation among the anatomical features that they pattern. To that end, I propose the following specific aims: 1) Understand how Scube family proteins modify hedgehog diffusion by tracking single particles of sonic hedgehog diffusing through the extracellular matrix. 2) Discover which biochemical features of a signaling protein affect its diffusion rate through the extracellular matrix by developing synthetic morphogens, in which diffusion can be uncoupled from downstream signal transduction. 3) Identify extracellular matrix modifiers of protein diffusion that contribute to tissue- or organism-specific signaling gradient size discrepancies by genetically simulating tissue-specific extracellular matrix variation K99/R00 Fellowship Application October 2022
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