Netrin-4 regulates thalamocortical axon branching in an activity-dependent fashion

• Published in: Proceedings of the National Academy of Sciences - PNAS 2014-10, Vol.111 (42), p.15226-15231
• Main Authors: Hayano, Yasufumi, Sasaki, Kensuke, Ohmura, Nami, Takemoto, Makoto, Maeda, Yurie, Yamashita, Toshihide, Hata, Yoshio, Kitada, Kazuhiro, Yamamoto, Nobuhiko
• Format: Article
• Language: English
• Subjects: Animals; Axons; Axons - metabolism; Axons - physiology; Behavioral neuroscience; Biological Sciences; Brain; Branching; Cells; Cerebral Cortex - metabolism; Cerebral Cortex - physiology; Coculture Techniques; Electroporation; Gene Expression Profiling; Gene Expression Regulation; HEK293 Cells; Heterozygote; Humans; Mice; Mice, Knockout; Molecules; Nerve Growth Factors - physiology; Netrins; Neurons; Neuroscience; Proteins; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface - metabolism; Rodents; Signal Transduction; Somatosensory cortex; Thalamus; Thalamus - metabolism; Thalamus - physiology; Visual cortex; Visual Cortex - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1402095111

Significance The environmental control of neuronal wiring is one of the most intriguing issues in neuroscience. However, the molecular mechanisms are largely unknown. Here, we demonstrate that the expression of the netrin family member netrin-4 (NTN4) is activity-dependent in the developing cortex and promotes terminal branching of thalamocortical axons. Evidence further shows that unc-5 homolog B (Unc5B), a putative receptor of NTN4, is expressed in the developing thalamus and mediates NTN4 signaling. These results suggest that NTN4 is the key molecule that underlies activity-dependent axon branch formation in neocortical circuits. Axon branching is remodeled by sensory-evoked and spontaneous neuronal activity. However, the underlying molecular mechanism is largely unknown. Here, we demonstrate that the netrin family member netrin-4 (NTN4) contributes to activity-dependent thalamocortical (TC) axon branching. In the postnatal developmental stages of rodents, ntn4 expression was abundant in and around the TC recipient layers of sensory cortices. Neuronal activity dramatically altered the ntn4 expression level in the cortex in vitro and in vivo. TC axon branching was promoted by exogenous NTN4 and suppressed by depletion of the endogenous protein. Moreover, unc-5 homolog B (Unc5B), which strongly bound to NTN4, was expressed in the sensory thalamus, and knockdown of Unc5B in thalamic cells markedly reduced TC axon branching. These results suggest that NTN4 acts as a positive regulator for TC axon branching through activity-dependent expression.