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How the environment affects humans is a very important research theme; however, how environmental factors affect neuronal wiring in the brain at the molecular level has been unknown. In the brain of a child during the development period, axons branching from neurons have terminal branching, connecting with target neurons. When there is active branching, axons connect with many neurons, but when branching is not so active, axons connect with a just few neurons. In this way, axon branching is important during the development period as it affects neuronal wiring functions. Abnormalities in this process may lead to functional disorders; however, the molecular mechanism for controlling axon branching has been unknown. In order clarify this intriguing issue, a group of researchers from Osaka University, Hokkaido University, and Tottori University studied the mechanism of axon branching occurring in thalamocortical projection.

Researchers at Osaka University:
• Cellular and Molecular Neurobiology Research Group, Graduate School of Frontier Biosciences, Osaka University -- HAYANO Yasufumi, Researcher (currently Graduate School of Medicine, Osaka University) and YAMAMOTO Nobuhiko, Professor

Regarding the formation of neuronal wiring, the foundation of brain functions, this group clarified that the protein netrin-4 (NTN4) secreted in the sensory region by visionary and auditory stimuli plays an important role in neuronal wiring during the development period. That is, NTN4 is made in the cerebral cortex after birth and promotes axon branching of thalamic neurons. This group has also found that far less axon branching occurred in the brain of mice lacking NTN expressing cells.

Furthermore, the amount of NTN4 in the cerebral cortex was found to be small in mice raised in darkness, but the amount increased in relation to optical stimulation. That is, the amount of NTN4 in postnatal development changed in relation to the level of environmental stimuli experienced. From these findings, the researchers clarified that visual stimuli deeply influenced the formation of neuronal wiring in the bran in the postnatal developmental stage.

This group's results have verified that not only are genetic factors important, but also exposure to appropriate stimuli in childhood contributes to normal brain development at the molecular level. These results are very important in understanding how the brain develops in childhood and will promote the understanding of environmental factors in neuropsychiatric disorders.


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.




To learn more about this research, please view the full research report entitled "Netrin-4 regulates thalamocortical axon branching in an activity-dependent fashion" at this page of the Proceedings of the National Academy of Sciences website.

Related link:

Yamamoto Lab., Cellular and Molecular Neurobiology Laboratory

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