Project Details
Projekt
Consequences of IFT-dynein-2 governed ciliary protein dynamics for skeletal development.
Applicant
Dr. Miriam Schmidts
Subject Area
Cell Biology
General Genetics and Functional Genome Biology
General Genetics and Functional Genome Biology
Term
since 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 503306912
Cilia represent tubulin-based antenna-like cellular structures extending from the surface of most vertebrate cells. As cilia have no protein synthesis capability, ciliary proteins are synthesized in the cytoplasm and trafficked into the cilium. Intraciliary protein transport along the axoneme is carried out by intraflagellar transport (IFT). IFT also transports protein complexes of the cytoplasmic pool from the cilium base into the cilium and vice versa. IFT regulation is highly dynamic, enabling fast adaptation to the rapidly changing cellular needs, including assembly and disassembly of cilia, and ciliary signal transduction upon mechanical or chemical stimuli with fast-changing IFT cargo. Over the past years, we and others have identified defective components of the dynein-2 complex, representing the motor for retrograde IFT from the tip to the base as well as defective IFT components as a major cause of ciliary chondrodysplasias. However, while clearly IFT-mediated intraciliary protein dynamics are essential for cellular differentiation, maintenance, and survival, individual functions of the IFT-dynein-2-complex components and their role in mammalian development have remained largely elusive. This is primarily due to the complete loss of cilia upon IFT or dynein-2 gene knockouts, preventing the analysis of individual IFT protein functions in cilia in those models. Specifically, while is has become evident over the last decade that IFT-governed ciliary protein dynamics are crucial for skeletal development, the contribution of individual IFT components to chondrocyte cilia protein dynamics, cell identity, and cell signaling as well as cartilage extracellular matrix establishment and skeletal development has not been understood. This project will dissect individual functions of ciliary IFT/dynein-2 complex components in regulating intraciliary protein dynamics and cilia assembly/disassembly and characterize the individual role of IFT/dynein-2 components in chondrocyte differentiation and skeletal development. To achieve this, we employ hypomorphic model systems carrying human disease alleles. This will not only advance our biological understanding of ciliary protein dynamics but hopefully also provide future therapeutic entry points for ciliary chondrodysplasias.
DFG Programme
Research Units
