Project Details
Projekt
The impact of cilium disassembly dynamics on developmental signaling
Applicants
Professor Dr. David Mick; Dr. Peter Walentek
Subject Area
Cell Biology
Biochemistry
Developmental Biology
Biochemistry
Developmental Biology
Term
since 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 503306912
The primary cilium is a solitary, dynamic plasma membrane micro-domain that orchestrates cellular signaling cascades with important functions in organismal development. A hallmark signaling pathway in primary cilia is Hedgehog signaling, the components of which dynamically localize to the primary cilium in a signaling-dependent manner to transmit morphogen information to the rest of the cell. However, signals can only be sensed when cells display primary cilia, which is tied to the cell cycle. Hedgehog morphogens regulate early embryonic development, including left-right axis patterning and neural tube closure with important implications for human health. Here, cells must receive signals to initiate cellular responses, followed by cilia removal to execute the initiated programs. As morphogens determine cell fates in a dose-dependent manner, signaling strength and duration are important parameters that specify signaling outputs. Yet, the relation of the dynamic removal of a cilium to the signaling response as well as the consequences of altered cilium removal on embryonic development remain largely unknown.In this project we will combine biochemical in vitro approaches with state-of-the-art developmental biology in the African Clawed Frog Xenopus laevis to study the relevance of the dynamic cilium removal for developmental signaling with a focus on Hedgehog signaling. Advanced proximity labeling technologies combined with quantitative mass spectrometry will determine the proteomic remodeling of the primary cilium during cilium removal to reveal the underlying molecular mechanisms and the consequences for cilia signaling on a molecular level. The significance of the dynamic behavior of ciliary signaling components during cilia removal for morphogenesis will be investigated in the left-right organizer and the developing neural tube in vivo. The main goals of the project are: 1) to reveal the molecular mechanisms of protein removal from cilia during cilium disassembly and how defects in this process impact cilia signaling, and 2) to understand how intraciliary Hedgehog dynamics affect cellular and tissue morphogenesis. We will thereby mechanistically resolve how alterations in cilia removal affect signaling and embryonic development across experimental systems in a comparative manner. The results will form the basis for future translational investigations focusing on human disease.
DFG Programme
Research Units
