image: Progranulin derived from Purkinje cells (PCs) counteracts synapse elimination and reinforces the strongest (winner) climbing fiber (CF). Progranulin acts on developing CF synapses from Postnatal day 11 to 16 independently of Semaphorin3A, another retrograde signaling molecule that counteracts CF synapse elimination. Progranulin derived from PCs acts retrogradely onto its putative receptor Sort1 on CFs. Loser CFs are maintained by progranulin-Sort1 signal and Semaphorin3A-PlexinA4 signal, but they are eventually pruned by "elimination signals" such as Semaphorin7A and brain-derived neurotrophic factor (BDNF). view more
Credit: 2018 Masanobu Kano.
Scientists from Japan have identified a molecule that aids a crucial "pruning" process in the brain that, if malfunctioning, could lead to disorders such as autism and dementia.
As the brain develops in utero and in early life, neurons and their connecting synapses branch out rapidly - like a tree. Over time, these connections become more refined and purposeful via a series of molecular mechanisms that prune the connections. Like a gardener trims a tree, weaker branches are discarded to redirect nutrients to help nurture the stronger branches.
However, genetic and environmental mutations can misguide this process and eliminate far too many synapses or not nearly enough. Either extreme can result in a myriad of neuropsychiatric disorders from autism spectrum disorder to schizophrenia to dementia.
The research team was led by Masanobu Kano, professor in the Department of Neurophysiology at the Graduate School of Medicine at the University of Tokyo.
The authors published their results today in the journal Neuron.
In a typically developing brain, a type of neuron called a Purkinje cell is furnished with climbing fibers. "Among multiple climbing fibers innervating each Purkinje cell in the neonatal cerebellum, a single climbing fiber is strengthened and maintained throughout an animal's life, whereas the other climbing fibers are weakened and eventually eliminated," Kano says. "Our goal was to identify a new molecule involved in strengthening and maintaining single climbing fiber inputs."
Kano and his team found that progranulin - a protein known to be involved in certain forms of dementia - also works to maintain developing climbing fiber inputs, counteracting the initial elimination. They studied a mouse model engineered without progranulin and found that climbing fibers were more quickly eliminated and climbing fiber input overall was significantly reduced.
"Our results provide a new insight into the roles of progranulin in the developing brain," says Kano. "We will continue to search molecules involved in synapse elimination in the developing cerebellum and, ultimately, we want to elucidate entire signaling cascades for synapse elimination."
Although the researchers do not yet know how to effectively manipulate the molecule, it's possible that progranulin signaling may be a potential therapeutic target for neuropsychiatric disorders.
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The team includes researchers from the Department of Cellular Neurobiology at the Brain Research Institute at Niigata University in Niigata, Japan; the Department of Anatomy at the Hokkaido University Graduate School of Medicine in Sapporo, Japan; and the International Research Center for Neurointelligence at the University of Tokyo Institutes for Advanced Study.
Journal article:
Naofumi Uesaka, Manabu Abe, Kohtarou Konno, Maya Yamazaki, Kazuto Sakoori, Takaki Watanabe, Tzu-Huei Kao, Takayasu Mikuni, Masahiko Watanabe, Kenji Sakimura and Masanobu Kano, Retrograde Signaling from Progranulin to Sort1 Counteracts Synapse Elimination in the Developing Cerebellum, Neuron
URL: https://dx.doi.org/10.1016/j.neuron.2018.01.018
DOI: 10.1016/j.neuron.2018.01.018
Collaborating institutions:
Niigata University
Hokkaido University
Link:
Research contact:
Professor Masanobu Kano
Department of Neurophysiology, Division of Functional Biology, Graduate School of Medicine, The University of Tokyo
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 JAPAN
Tel: +81-3-5841-3538
Fax: +81-3-5802-3315
Email: mkano-tky@m.u-tokyo.ac.jp
Press officer contact:
Tetsushi Kagawa, Ph.D.
International Research Center for Neurointelligence (WPI-IRCN)
The University of Tokyo
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 JAPAN
Tel: +81-3-5841-3014
Email: kagawa.tetsushi@mail.u-tokyo.ac.jp
Funding:
This work was supported by Grants-in-Aid for Scientific Research from JSPS, Japan, by Brain/MINDS from MEXT and AMED, Japan, and by SRPBS from AMED, Japan.
About the International Research Center for Neurointelligence (IRCN)
The IRCN was established in October 2017, supported by the World Premier International Research Center Initiative (WPI) program of the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan. The IRCN aims to create a new discipline of neurointelligence, fusing the life sciences, medicine, and information sciences. The center's goal is to discover new principles of neural circuit development to drive the creation of innovative artificial intelligence (AI) technologies, understand psychiatric disorders, and nurture young international AI-neuroscientists.
About the University of Tokyo
The University of Tokyo is Japan's leading university and one of the world's top research universities. The vast research output of some 6,000 researchers is published in the world's top journals across the arts and sciences. Our vibrant student body of around 15,000 undergraduate and 15,000 graduate students includes over 2,000 international students. Find out more at http://www.u-tokyo.ac.jp/en/ or follow us on Twitter at @UTokyo_News_en.
Journal
Neuron