SorCS2 binds progranulin to regulate motor neuron development

Motor neuron (MN) development and nerve regeneration requires orchestrated action of a vast number of molecules. Here, we identify SorCS2 as a progranulin (PGRN) receptor that is required for MN diversification and axon outgrowth in zebrafish and mice. In zebrafish, SorCS2 knockdown also affects neu...

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Published in:	Cell reports (Cambridge) Vol. 42; no. 11; p. 113333
Main Authors:	Thomasen, Pernille Bogetofte, Salasova, Alena, Kjaer-Sorensen, Kasper, Woloszczuková, Lucie, Lavický, Josef, Login, Hande, Tranberg-Jensen, Jeppe, Almeida, Sergio, Beel, Sander, Kavková, Michaela, Qvist, Per, Kjolby, Mads, Ovesen, Peter Lund, Nolte, Stella, Vestergaard, Benedicte, Udrea, Andreea-Cornelia, Nejsum, Lene Niemann, Chao, Moses V., Van Damme, Philip, Krivanek, Jan, Dasen, Jeremy, Oxvig, Claus, Nykjaer, Anders
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 28-11-2023 Elsevier
Subjects:	Animals CP: Developmental biology CP: Neuroscience Granulins image segmentation Intercellular Signaling Peptides and Proteins light-sheet microscopy Mice Mice, Knockout motor neurons Motor Neurons - metabolism nerve injury Nerve Tissue Proteins - metabolism neurodevelopment neurotrophic signaling progranulin Progranulins Receptors, Cell Surface - metabolism SorCS2 VPS10p-D receptors zebrafish Zebrafish - metabolism motor neurons VPS10p-D receptors neurodevelopment image segmentation CP: Neuroscience nerve injury progranulin zebrafish CP: Developmental biology neurotrophic signaling light-sheet microscopy SorCS2
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Summary:	Motor neuron (MN) development and nerve regeneration requires orchestrated action of a vast number of molecules. Here, we identify SorCS2 as a progranulin (PGRN) receptor that is required for MN diversification and axon outgrowth in zebrafish and mice. In zebrafish, SorCS2 knockdown also affects neuromuscular junction morphology and fish motility. In mice, SorCS2 and PGRN are co-expressed by newborn MNs from embryonic day 9.5 until adulthood. Using cell-fate tracing and nerve segmentation, we find that SorCS2 deficiency perturbs cell-fate decisions of brachial MNs accompanied by innervation deficits of posterior nerves. Additionally, adult SorCS2 knockout mice display slower motor nerve regeneration. Interestingly, primitive macrophages express high levels of PGRN, and their interaction with SorCS2-positive motor axon is required during axon pathfinding. We further show that SorCS2 binds PGRN to control its secretion, signaling, and conversion into granulins. We propose that PGRN-SorCS2 signaling controls MN development and regeneration in vertebrates. [Display omitted] •SorCS2 controls motor neuron cell-fate decisions, axon outgrowth, and synapse morphology•SorCS2 deficiency impairs behavior of primitive macrophages associated with motor axons•SorCS2 is a PGRN receptor required for its neurotrophic signaling in motor neurons•SorCS2 binds PGRN to regulate its trafficking, secretion, and conversion to mature granulins Thomasen et al. use various vertebrate models to assess the function of SorCS2 receptor in motor neuron development and regeneration. They describe that SorCS2 regulates motor neuron identity, synapse architecture, and motor nerve innervation via its binding to progranulin. Intracellularly, this interaction further determines progranulin secretion, sorting, and cleavage.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2211-1247 2211-1247
DOI:	10.1016/j.celrep.2023.113333