Molecular mechanisms driving muscle dedifferentiation during muscle lineage reprogramming

• Applicant: Professorin Dr. Wiebke Herzog, since 9/2021
• Subject Area: Developmental Biology
• Term: from 2017 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 391299137

How stable are differentiation states of cells and which factors and mechanisms have the power to alter or revoke them? The metamorphosing Drosophila somatic musculature represents an ideal system to analyse these questions. During metamorphosis the anterior three pairs of embryonic alary muscles undergo a direct lineage reprogramming process into another type of somatic muscle, the ventral longitudinal muscles (VLM). This process is initiated by the induction of molecular events that lead to the dedifferentiation of the syncytial alary muscles into mononucleate myoblasts that later will redifferentiate into the VLM. Although some of the players initiating this intriguing process have already been identified, the exact molecular mechanisms that drive alary muscle dedifferentiation remain unclear. In order to extend our understanding of the mechanisms that guide alary muscle dedifferentiation, and in vivo muscle dedifferentiation processes in general we are addressing different aspects and regulatory instances of the dedifferentiation process: 1. Characterizing the role of twist during induction of muscle dedifferentiation. The function of this highly conserved bHLH transcription factor has been linked in vitro to muscle dedifferentiation processes in vertebrates. Decoding its operating mode during alary muscle dedifferentiation will add new links to a transcriptional regulatory framework that is guiding muscle dedifferentiation in vivo.2. Dissecting the connection of the Hippo pathway to muscle dedifferentiation. The current state of research associates the Hippo pathway in vertebrates and Drosophila primarily with organ size control by regulating cell proliferation, apoptosis, and stem cell renewal. Deciphering its role during alary muscle dedifferentiation will enhance our understanding of how differentiation states are realized or reversed by context dependent modulation of Hippo pathway activity. 3. Elucidating the role of programmed cell death responses during muscle dedifferentiation. The role of programmed cell death (PCD) responses during muscle dedifferentiation processes has been analysed to date mainly in vitro and after forced dedifferentiation. Analyses of the role of caspases during alary muscle lineage reprogramming will provide new insights into programmed cell death response functions and apoptosis interception during a naturally occurring muscle dedifferentiation process.4. Revealing the role of autophagic processes during muscle dedifferentiation.Autophagy plays a critical homeostatic role in post-mitotic differentiated skeletal muscle cells and was recently connected in vertebrates to dedifferentiation processes in vitro. The characterization of factors and mechanisms that induce and execute autophagic processes during alary muscle lineage reprogramming will uncover new functions for autophagy and the autophagy-related genes during an in vivo muscle dedifferentiation processes

• DFG Programme: Research Grants
• Ehemaliger Antragsteller: Dr. Christoph Schaub, until 9/2021