Exosome-mediated cell-cell communication in Rett Syndrome Development of functional neuronal circuits requires a complex series of events involving coordinated communication between multiple cell types over multiple dimensions of space and time. Extracellular membrane vesicles (EMVs), specifically exosomes, may serve as a novel form of cell-cell communication during brain development. Exosomes can transfer bioactive lipids, proteins, and RNAs between cells without requiring direct contact between the donor and recipient cells. So far, no studies have demonstrated that exosomes play a role in brain development or that deficits in exosome signaling might underlie neurodevelopmental disorders such as Rett Syndrome. We propose to address these fundamental open questions regarding the potential role of exosomes in brain circuit development in Rett Syndrome and healthy neurons using both mouse and hiPSC models.
Basic mechanisms controlling brain development and how they go awry in neurodevelopmental diseases remain a mystery. The potential role of exosomes as a novel intercellular signaling mechanism in the development and maintenance of healthy brain circuits will have broad relevance to human neurological disorders. PUBLIC HEALTH RELEVANCE: The function of exosomes in inter-cellular communication in the nervous system is relatively unexplored. Here we propose experiments to determine whether exosomes released from neural cells regulate the development and maintenance of connections in the nervous system and whether this signaling function is deficient in Rett Syndrome.
|Beltrão-Braga, Patricia C B; Muotri, Alysson R (2017) Modeling autism spectrum disorders with human neurons. Brain Res 1656:49-54|
|de Souza, Janaina S; Carromeu, Cassiano; Torres, Laila B et al. (2017) IGF1 neuronal response in the absence of MECP2 is dependent on TRalpha 3. Hum Mol Genet 26:270-281|
|Herai, Roberto H; Negraes, Priscilla D; Muotri, Alysson R (2017) Evidence of nuclei-encoded spliceosome mediating splicing of mitochondrial RNA. Hum Mol Genet 26:2590|
|Herai, Roberto H; Negraes, Priscilla D; Muotri, Alysson R (2017) Evidence of nuclei-encoded spliceosome mediating splicing of mitochondrial RNA. Hum Mol Genet 26:2472-2479|
|Pillat, Micheli M; Lameu, Claudiana; Trujillo, Cleber A et al. (2016) Bradykinin promotes neuron-generating division of neural progenitor cells through ERK activation. J Cell Sci 129:3437-48|
|Chailangkarn, Thanathom; Trujillo, Cleber A; Freitas, Beatriz C et al. (2016) A human neurodevelopmental model for Williams syndrome. Nature 536:338-43|
|Vessoni, Alexandre T; Herai, Roberto H; Karpiak, Jerome V et al. (2016) Cockayne syndrome-derived neurons display reduced synapse density and altered neural network synchrony. Hum Mol Genet 25:1271-80|
|Tang, Xin; Kim, Julie; Zhou, Li et al. (2016) KCC2 rescues functional deficits in human neurons derived from patients with Rett syndrome. Proc Natl Acad Sci U S A 113:751-6|
|Brennand, Kristen J; Marchetto, M Carol; Benvenisty, Nissim et al. (2015) Creating Patient-Specific Neural Cells for the In Vitro Study of Brain Disorders. Stem Cell Reports 5:933-945|
|Sharma, Pranav; Schiapparelli, Lucio; Cline, Hollis T (2013) Exosomes function in cell-cell communication during brain circuit development. Curr Opin Neurobiol 23:997-1004|