Retrograde Signaling from Progranulin to Sort1 Counteracts Synapse Elimination in the Developing Cerebellum

• Published in: Neuron (Cambridge, Mass.) Mass.), 2018-02, Vol.97 (4), p.796-805.e5
• Main Authors: Uesaka, Naofumi, Abe, Manabu, Konno, Kohtarou, Yamazaki, Maya, Sakoori, Kazuto, Watanabe, Takaki, Kao, Tzu-Huei, Mikuni, Takayasu, Watanabe, Masahiko, Sakimura, Kenji, Kano, Masanobu
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Vesicular Transport - physiology; Animals; Cerebellum; Cerebellum - growth & development; climbing fiber; Dementia; Dementia disorders; Dendrites - physiology; Excitatory Postsynaptic Potentials; Female; Frontotemporal dementia; Functional morphology; Genes; Growth factors; HEK293 Cells; Humans; Intercellular Signaling Peptides and Proteins - physiology; Male; Mice, Inbred C57BL; Mice, Transgenic; mouse; Neonates; Neural networks; Neuronal Plasticity; postnatal development; progranulin; Progranulins - physiology; Purkinje cell; Purkinje cells; Purkinje Cells - physiology; Rats, Sprague-Dawley; retrograde signal; Retrograde transport; Rodents; Semaphorin-3A - physiology; Signal Transduction; Sort1; Synapse elimination; Synapses; Synapses - physiology; Synaptogenesis
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2018.01.018

Elimination of redundant synapses formed early in development and strengthening of necessary connections are crucial for shaping functional neural circuits. Purkinje cells (PCs) in the neonatal cerebellum are innervated by multiple climbing fibers (CFs) with similar strengths. A single CF is strengthened whereas the other CFs are eliminated in each PC during postnatal development. The underlying mechanisms, particularly for the strengthening of single CFs, are poorly understood. Here we report that progranulin, a multi-functional growth factor implicated in the pathogenesis of frontotemporal dementia, strengthens developing CF synaptic inputs and counteracts their elimination from postnatal day 11 to 16. Progranulin derived from PCs acts retrogradely onto its putative receptor Sort1 on CFs. This effect is independent of semaphorin 3A, another retrograde signaling molecule that counteracts CF synapse elimination. We propose that progranulin-Sort1 signaling strengthens and maintains developing CF inputs, and may contribute to selection of single “winner” CFs that survive synapse elimination. •Progranulin is a PC-derived regulator of developmental CF synapse elimination•Progranulin from PCs counteracts synapse elimination and reinforces the strongest CF•Progranulin acts on developing CF synapses from P11 to P16 independently of Sema3A•Sort1 on CFs mediates the retrograde action of progranulin on CF synapse elimination Neural circuits are sculpted by eliminating redundant synapses and strengthening necessary connections depending on retrograde signals from postsynaptic neurons. Uesaka et al. demonstrate that progranulin, a multi-functional growth factor implicated in frontotemporal dementia, mediates retrograde signaling to counteract synapse elimination.