Thursday, December 26, 2024
12/26/2024
Abstract Apical extracellular matrix (aECM) coats the outward-facing surface of every organ, forming a barrier between the organism and its environment. Although it has been viewed historically as a static layer, aECM has been recently revealed to be dynamic across development and highly varied between cell types. It plays important roles in shaping organ morphogenesis and modulating cell activity. Identifying the regulatory mechanisms that control aECM composition and structure is therefore critical to understanding its role in development. Further, because aECM is highly accessible, there is enormous potential to manipulate it for targeted delivery of therapeutics or in tissue engineering. The major obstacles to studying aECM remodeling are that changes in aECM are difficult to visualize and need to be studied in vivo during highly dynamic processes that involve complex cell rearrangements. This project overcomes these obstacles by using an innovative model of developmentally programmed aECM remodeling. Preliminary data lead to the hypothesis that aECM structure is a discrete modular feature of cell identity, analogous to neurotransmitter types in neurons, rather than a continuum of stiffness/density. The C. elegans cuticle is an aECM that forms barrier between the animal and its environment. In order to directly access the external environment, the ciliated endings of some sensory neurons protrude through nanoscale pores in the cuticle, while those of other sensory neurons are embedded in specialized sheets of cuticle. Both types of cuticle structure are produced by glial cells that wrap the sensory neuron endings. One of these glial cells offers a remarkable example of developmentally programmed aECM remodeling: in juveniles of both sexes and in adult hermaphrodites it produces a cuticle sheet, but in adult males it produces a cuticle pore. This represents a discrete aECM remodeling event that occurs at a defined developmental stage without any major cell rearrangements. Preliminary data show that this aECM remodeling event is accompanied by a switch in gene expression in the glial cell. This includes expression of GRL-18, a novel class of aECM component that forms nanoscale rings in the cuticle. These observations leads to the hypothesis that a developmentally regulated switch in gene expression induces remodeling of aECM to form a nanoscale pore. To test this hypothesis, this project will (Aim 1) use mutant analysis and transcriptional profiling to define the gene expression switch that accompanies aECM remodeling; (Aim 2) determine how a novel developmentally regulated protein (GRL-18) contributes to aECM structure; and (Aim 3) test if changes in expression of GRL-18 and co-regulated genes are sufficient to remodel aECM into a nanoscale pore.
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