Dissecting Ret receptor signaling in space-filling dendrite patterning in Drosophila
Molecular Biology and Physiology of Neurons and Glial Cells
Final Report Abstract
Neurons develop class-specific morphologies by patterning their cellular processes, in particular their dendrites, in a stereotyped manner. Besides cell-autonomous mechanisms that regulate the intrinsic capacity of neurons to grow a dendritic tree of a defined shape and complexity, extrinsic mechanisms also direct dendritic growth and ensure proper innervation of their receptive field. How this is achieved at the mechanistic level is still under intense investigation. Further insight into the underlying molecular mechanisms is therefore essential to understand the basic principles of neuronal dendrite morphogenesis and network formation. Our work provided insight into how a substrate-derived ligand, the secreted TGFß Maverick (Mav), is providing a local growth cue that stabilizes dendrite growth to ensure space-filling coverage of sensory neuron dendrites in Drosophila. Extrinsically derived Mav is taken up by growing dendrites depending on the presence of its receptor Ret. Our data suggest that not yet covered regions have higher Mav levels and thus offer an attractive growth substrate for dendrites. Local attraction and stabilization of dendrites by Mav promotes dendrite growth and stability in uncovered regions and ensures that the receptive field of these neurons is space-filling. Our study thus provided a novel mechanistic model how space-filling dendrite growth can be achieved through the action of a local and proximally acting substrate-derived ligand. While the intracellular signaling mechanism of Ret and Mav-mediated space-filling dendrite growth remains to be fully uncovered, our related work on the conserved kinase Tao unveiled its function as a negative regulator of dendrite growth in the Drosophila larval nociceptive circuit. Tao kinase activity is tightly regulated during neuronal dendrite development and controls the density of dendritic and synaptic innervation as well as neuronal network connectivity. Our work showed that deregulation of Tao function resulted in network changes affecting neuronal responses and escape behavior in Drosophila. Interestingly, its human orthologue Tao kinase 2 (hTAOK2) could functionally replace Drosophila Tao and rescue all aspects of connectivity and behavior. However, our work also showed that an Autism-linked patient variant of TAOK2 was non-functional suggesting that analogous changes in sensory network connectivity play a role in Autism Spectrum Disorders.
Publications
- (2018). Ret and substrate-derived TGFß maverick regulate space-filling dendrite growth in Drosophila sensory neurons. Cell Rep 24: 2261-2272
Hoyer N, Zielke P, Hu C, Petersen M, Sauter K, Scharrenberg R, Peng Y, Kim CC, Han C, Parrish JZ, Soba P
(See online at https://doi.org/10.1016/j.celrep.2018.07.092) - (2019). Maintenance of cell type-specific connectivity and circuit function requires Tao kinase. Nat Comm 10(1), 3506
Tenedini FM, Saéz Gonzáles M, Hu C, Pedersen L, Petruzzi MM, Wang D, Richter M, Petersen M, Spotowicz E, Schweizer M, Sigrist S, Calderon de Anda F, Soba P
(See online at https://doi.org/10.1038/s41467-019-11408-1) - (2020) Antinociceptive modulation by the adhesion GPCR CIRL promotes mechanosensory signal discrimination. eLife 9: e56738
Dannhäuser S, Lux TJ, Hu C, Selcho M, Chen JT-C, Ehmann N, Sachidanandan D, Stopp S, Pauls D, Pawlak M, Langenhan T, Soba P, Rittner HL, Kittel RJ
(See online at https://doi.org/10.7554/elife.56738) - (2021) Optogenetic delivery of trophic signals in a genetic model of Parkinson's disease. PLoS Genet 17:e1009479
Ingles-Prieto A, Furthmann N, Crossman SH, Tichy AM, Hoyer N, Petersen M, Zheden V, Biebl J, Reichhart E, Gyoergy A, Siekhaus DE, Soba P, Winklhofer KF, Janovjak H
(See online at https://doi.org/10.1371/journal.pgen.1009479)
