TY - JOUR
T1 - SorCS2 binds progranulin to regulate motor neuron development
AU - Thomasen, Pernille Bogetofte
AU - Salasova, Alena
AU - Kjaer-Sorensen, Kasper
AU - Woloszczuková, Lucie
AU - Lavický, Josef
AU - Login, Hande
AU - Tranberg-Jensen, Jeppe
AU - Almeida, Sergio
AU - Beel, Sander
AU - Kavková, Michaela
AU - Qvist, Per
AU - Kjolby, Mads
AU - Ovesen, Peter Lund
AU - Nolte, Stella
AU - Vestergaard, Benedicte
AU - Udrea, Andreea-Cornelia
AU - Nejsum, Lene Niemann
AU - Chao, Moses V
AU - Van Damme, Philip
AU - Krivanek, Jan
AU - Dasen, Jeremy
AU - Oxvig, Claus
AU - Nykjaer, Anders
PY - 2023/11
Y1 - 2023/11
N2 - 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.
AB - 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.
KW - CP: Developmental biology
KW - CP: Neuroscience
KW - SorCS2
KW - VPS10p-D receptors
KW - image segmentation
KW - light-sheet microscopy
KW - motor neurons
KW - nerve injury
KW - neurodevelopment
KW - neurotrophic signaling
KW - progranulin
KW - zebrafish
KW - Zebrafish/metabolism
KW - Progranulins
KW - Intercellular Signaling Peptides and Proteins
KW - Granulins
KW - Motor Neurons/metabolism
KW - Mice, Knockout
KW - Animals
KW - Nerve Tissue Proteins/metabolism
KW - Receptors, Cell Surface/metabolism
KW - Mice
UR - http://www.scopus.com/inward/record.url?scp=85176089530&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2023.113333
DO - 10.1016/j.celrep.2023.113333
M3 - Journal article
C2 - 37897724
SN - 2211-1247
VL - 42
JO - Cell Reports
JF - Cell Reports
IS - 11
M1 - 113333
ER -