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Proc Natl Acad Sci U S A. 2019 Aug 6;116(32):16086-16094. doi: 10.1073/pnas.1902513116. Epub 2019 Jul 18.

Exosomes regulate neurogenesis and circuit assembly.

Author information

1
Neuroscience Department, The Scripps Research Institute, La Jolla, CA 92093.
2
The Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92093.
3
Department of Pediatrics/Rady Children's Hospital San Diego, University of California San Diego School of Medicine, La Jolla, CA 92093.
4
Department of Cellular & Molecular Medicine, University of California San Diego School of Medicine, La Jolla, CA 92093.
5
Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92093.
6
Kavli Institute for Brain and Mind, University of California San Diego, La Jolla, CA 92093.
7
Center for Academic Research and Training in Anthropogeny, La Jolla, CA 92093.
8
Neuroscience Department, The Scripps Research Institute, La Jolla, CA 92093; cline@scripps.edu.

Abstract

Exosomes are thought to be released by all cells in the body and to be involved in intercellular communication. We tested whether neural exosomes can regulate the development of neural circuits. We show that exosome treatment increases proliferation in developing neural cultures and in vivo in dentate gyrus of P4 mouse brain. We compared the protein cargo and signaling bioactivity of exosomes released by hiPSC-derived neural cultures lacking MECP2, a model of the neurodevelopmental disorder Rett syndrome, with exosomes released by isogenic rescue control neural cultures. Quantitative proteomic analysis indicates that control exosomes contain multiple functional signaling networks known to be important for neuronal circuit development. Treating MECP2-knockdown human primary neural cultures with control exosomes rescues deficits in neuronal proliferation, differentiation, synaptogenesis, and synchronized firing, whereas exosomes from MECP2-deficient hiPSC neural cultures lack this capability. These data indicate that exosomes carry signaling information required to regulate neural circuit development.

KEYWORDS:

Rett syndrome; exosomes; extracellular vesicle; neuronal development; synaptogenesis

Conflict of interest statement

Conflict of interest statement: The authors declare a conflict of interest. A.R.M. is a cofounder and has equity interest in TISMOO, a company dedicated to genetic analysis focusing on therapeutic applications customized for autism spectrum disorder and other neurological disorders with genetic origins. The terms of this arrangement have been reviewed and approved by the University of California San Diego, in accordance with its conflict of interest policies. The remaining authors declare that they have no conflict of interest.

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