{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T20:12:15Z","timestamp":1789157535272,"version":"build-2803163510"},"reference-count":49,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2021,3,11]],"date-time":"2021-03-11T00:00:00Z","timestamp":1615420800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100002736","name":"Citizens United for Research in Epilepsy","doi-asserted-by":"publisher","award":["CURE innovator award"],"award-info":[{"award-number":["CURE innovator award"]}],"id":[{"id":"10.13039\/100002736","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009670","name":"National Alliance for Research on Schizophrenia and Depression","doi-asserted-by":"publisher","award":["NARSAD Distinguished investigator award"],"award-info":[{"award-number":["NARSAD Distinguished investigator award"]}],"id":[{"id":"10.13039\/100009670","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001771","name":"Tuberous Sclerosis Alliance","doi-asserted-by":"publisher","award":["Investigator award"],"award-info":[{"award-number":["Investigator award"]}],"id":[{"id":"10.13039\/100001771","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Rab27a is an evolutionarily conserved small GTPase that regulates vesicle trafficking, and copy number variants of RAB27a are associated with increased risk of autism. However, the function of Rab27a on brain development is unknown. Here, we identified a form of paracrine communication that regulates spine development between distinct populations of developing cortical neurons. In the developing somatosensory cortex of mice, we show that decreasing Rab27a levels in late-born pyramidal neurons destined for layer (L) 2\/3 had no cell-autonomous effect on their synaptic integration but increased excitatory synaptic transmission onto L4 neurons that receive somatosensory information. This effect resulted in an increased number of L4 neurons activated by whisker stimulation in juvenile mice. In addition, we found that Rab27a, the level of which decreases as neurons mature, regulates the release of small extracellular vesicles (sEVs) in developing neurons in vitro and decreasing Rab27a levels led to the accumulation of CD63-positive vesicular compartments in L2\/3 neurons in vivo. Together, our study reveals that Rab27a-mediated paracrine communication regulates the development of synaptic connectivity, ultimately tuning responses to sensory stimulation, possibly via controlling the release of sEVs.<\/jats:p>","DOI":"10.3390\/cells10030622","type":"journal-article","created":{"date-parts":[[2021,3,11]],"date-time":"2021-03-11T20:17:40Z","timestamp":1615493860000},"page":"622","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Rab27a-Dependent Paracrine Communication Controls Dendritic Spine Formation and Sensory Responses in the Barrel Cortex"],"prefix":"10.3390","volume":"10","author":[{"given":"Longbo","family":"Zhang","sequence":"first","affiliation":[{"name":"Departments of Neurosurgery, and Cellular &amp; Molecular Physiology, School of Medicine, Yale University, 333 Cedar Street, New Haven, CT 06520-8082, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5707-193X","authenticated-orcid":false,"given":"Xiaobing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Psychology, Florida State University, Tallahassee, FL 32306, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lawrence S.","family":"Hsieh","sequence":"additional","affiliation":[{"name":"Departments of Neurosurgery, and Cellular &amp; Molecular Physiology, School of Medicine, Yale University, 333 Cedar Street, New Haven, CT 06520-8082, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiffany V.","family":"Lin","sequence":"additional","affiliation":[{"name":"Departments of Neurosurgery, and Cellular &amp; Molecular Physiology, School of Medicine, Yale University, 333 Cedar Street, New Haven, CT 06520-8082, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3496-3385","authenticated-orcid":false,"given":"Ang\u00e9lique","family":"Bordey","sequence":"additional","affiliation":[{"name":"Departments of Neurosurgery, and Cellular &amp; Molecular Physiology, School of Medicine, Yale University, 333 Cedar Street, New Haven, CT 06520-8082, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,11]]},"reference":[{"key":"ref_1","first-page":"3171","article-title":"Cellular functions of Rab GTPases at a glance","volume":"128","author":"Zhen","year":"2015","journal-title":"J. Cell Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1152\/physrev.00059.2009","article-title":"Role of Rab GTPases in membrane traffic and cell physiology","volume":"91","author":"Hutagalung","year":"2011","journal-title":"Physiol. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1091\/mbc.e16-10-0737","article-title":"Rab GTPases: Master regulators that establish the secretory and endocytic pathways","volume":"28","author":"Pfeffer","year":"2017","journal-title":"Mol. Biol. Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/S1471-4914(01)02227-4","article-title":"Rab GTPases, intracellular traffic and disease","volume":"8","author":"Seabra","year":"2002","journal-title":"Trends Mol. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2801","DOI":"10.1007\/s00018-008-8351-4","article-title":"Regulation of secretory vesicle traffic by Rab small GTPases","volume":"65","author":"Fukuda","year":"2008","journal-title":"Cell Mol. Life Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"R471","DOI":"10.1016\/j.cub.2018.02.010","article-title":"Rab GTPases and Membrane Trafficking in Neurodegeneration","volume":"28","author":"Kiral","year":"2018","journal-title":"Curr. Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1038\/76024","article-title":"Mutations in RAB27A cause Griscelli syndrome associated with haemophagocytic syndrome","volume":"25","author":"Menasche","year":"2000","journal-title":"Nat. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1002\/pbc.22357","article-title":"Clinical presentation of Griscelli syndrome type 2 and spectrum of RAB27A mutations","volume":"54","author":"Meeths","year":"2010","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1016\/j.ajhg.2013.07.024","article-title":"Transmission disequilibrium of small CNVs in simplex autism","volume":"93","author":"Krumm","year":"2013","journal-title":"Am. J. Hum. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2617","DOI":"10.1091\/mbc.e05-12-1170","article-title":"Regulation of synaptic transmission by RAB-3 and RAB-27 in Caenorhabditis elegans","volume":"17","author":"Mahoney","year":"2006","journal-title":"Mol. Biol. Cell."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"16003","DOI":"10.1073\/pnas.0804825105","article-title":"Role of Rab27 in synaptic transmission at the squid giant synapse","volume":"105","author":"Yu","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1704","DOI":"10.1016\/j.cub.2011.08.058","article-title":"Systematic discovery of Rab GTPases with synaptic functions in Drosophila","volume":"21","author":"Chan","year":"2011","journal-title":"Curr. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1038\/nn.3332","article-title":"mRNA expression, splicing and editing in the embryonic and adult mouse cerebral cortex","volume":"16","author":"Dillman","year":"2013","journal-title":"Nat. Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1038\/nature13185","article-title":"Transcriptional landscape of the prenatal human brain","volume":"508","author":"Miller","year":"2014","journal-title":"Nature"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1038\/ncb2000","article-title":"Rab27a and Rab27b control different steps of the exosome secretion pathway","volume":"12","author":"Ostrowski","year":"2010","journal-title":"Nat. Cell Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1038\/ncb2530","article-title":"Get on the exosome bus with ALIX","volume":"14","author":"Hurley","year":"2012","journal-title":"Nat. Cell Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.ceb.2014.05.004","article-title":"Biogenesis and secretion of exosomes","volume":"29","author":"Kowal","year":"2014","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1038\/ncb1596","article-title":"Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells","volume":"9","author":"Valadi","year":"2007","journal-title":"Nat. Cell Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"R125","DOI":"10.1093\/hmg\/dds317","article-title":"Exosomes and microvesicles: Extracellular vesicles for genetic information transfer and gene therapy","volume":"21","author":"Lee","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"ref_20","first-page":"481","article-title":"Extracellular Vesicles: Evolutionarily Conserved Mediators of Intercellular Communication","volume":"90","author":"Lawson","year":"2017","journal-title":"Yale J. Biol. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1042\/EBC20170076","article-title":"To be or not to be... secreted as exosomes, a balance finely tuned by the mechanisms of biogenesis","volume":"62","author":"Palmulli","year":"2018","journal-title":"Essays Biochem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3434","DOI":"10.1038\/s41467-018-05858-2","article-title":"Reciprocal control of excitatory synapse numbers by Wnt and Wnt inhibitor PRR7 secreted on exosomes","volume":"9","author":"Lee","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"16086","DOI":"10.1073\/pnas.1902513116","article-title":"Exosomes regulate neurogenesis and circuit assembly","volume":"116","author":"Sharma","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1198","DOI":"10.1172\/JCI81134","article-title":"Extracellular vesicles and intercellular communication within the nervous system","volume":"126","author":"Zappulli","year":"2016","journal-title":"J. Clin. Investig."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1038\/nrn.2015.29","article-title":"Extracellular vesicles round off communication in the nervous system","volume":"17","author":"Budnik","year":"2016","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"11330","DOI":"10.1073\/pnas.1605740113","article-title":"Normalizing translation through 4E-BP prevents mTOR-driven cortical mislamination and ameliorates aberrant neuron integration","volume":"113","author":"Lin","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Pathania, M., Torres-Reveron, J., Yan, L., Kimura, T., Lin, T.V., Gordon, V., Teng, Z.Q., Zhao, X., Fulga, T.A., and Van, V.D. (2012). miR-132 enhances dendritic morphogenesis, spine density, synaptic integration, and survival of newborn olfactory bulb neurons. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0038174"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Rodriguez, A., Ehlenberger, D.B., Dickstein, D.L., Hof, P.R., and Wearne, S.L. (2008). Automated three-dimensional detection and shape classification of dendritic spines from fluorescence microscopy images. PLoS ONE, 3.","DOI":"10.1371\/journal.pone.0001997"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1038\/embor.2012.102","article-title":"Dendritic spines: From structure to in vivo function","volume":"13","author":"Rochefort","year":"2012","journal-title":"EMBO Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.neuron.2014.09.009","article-title":"MEK-ERK1\/2-Dependent FLNA Overexpression Promotes Abnormal Dendritic Patterning in Tuberous Sclerosis Independent of mTOR","volume":"84","author":"Zhang","year":"2014","journal-title":"Neuron"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"10380","DOI":"10.1073\/pnas.0403954101","article-title":"Cre-lox-regulated conditional RNA interference from transgenes","volume":"101","author":"Ventura","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1111\/j.1469-7793.1999.00169.x","article-title":"Reliable synaptic connections between pairs of excitatory layer 4 neurones within a single \u2019barrel\u2019 of developing rat somatosensory cortex","volume":"521","author":"Feldmeyer","year":"1999","journal-title":"J. Physiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"aac9462","DOI":"10.1126\/science.aac9462","article-title":"Principles of connectivity among morphologically defined cell types in adult neocortex","volume":"350","author":"Jiang","year":"2015","journal-title":"Science"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1007\/s00424-003-1167-z","article-title":"The barrel cortex--integrating molecular, cellular and systems physiology","volume":"447","author":"Petersen","year":"2003","journal-title":"Pflugers Arch"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/S0891-0618(01)00155-7","article-title":"Expression of c-Fos, ICER, Krox-24 and JunB in the whisker-to-barrel pathway of rats: Time course of induction upon whisker stimulation by tactile exploration of an enriched environment","volume":"23","author":"Bisler","year":"2002","journal-title":"J. Chem. Neuroanat."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/j.pneurobio.2011.01.003","article-title":"Multivesicular bodies in neurons: Distribution, protein content, and trafficking functions","volume":"93","author":"Altick","year":"2011","journal-title":"Prog. Neurobiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1016\/j.cell.2019.02.029","article-title":"Reassessment of Exosome Composition","volume":"177","author":"Jeppesen","year":"2019","journal-title":"Cell"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1038\/s41556-018-0040-4","article-title":"Identification of distinct nanoparticles and subsets of extracellular vesicles by asymmetric flow field-flow fractionation","volume":"20","author":"Zhang","year":"2018","journal-title":"Nat. Cell Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1862","DOI":"10.1126\/science.308.5730.1862","article-title":"Cell biology: The ins and outs of exosomes","volume":"308","author":"Couzin","year":"2005","journal-title":"Science"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.1016\/j.bbamem.2016.02.011","article-title":"Exosomes and other extracellular vesicles in neural cells and neurodegenerative diseases","volume":"1858","author":"Janas","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1038\/nri2567","article-title":"Membrane vesicles as conveyors of immune responses","volume":"9","author":"Thery","year":"2009","journal-title":"Nat. Rev. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Dujardin, S., Begard, S., Caillierez, R., Lachaud, C., Delattre, L., Carrier, S., Loyens, A., Galas, M.C., Bousset, L., and Melki, R. (2014). Ectosomes: A new mechanism for non-exosomal secretion of tau protein. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0100760"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2112","DOI":"10.1038\/nprot.2012.131","article-title":"Exosome-mediated delivery of siRNA in vitro and in vivo","volume":"7","author":"Lee","year":"2012","journal-title":"Nat. Protoc."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"24420","DOI":"10.1074\/jbc.270.41.24420","article-title":"Deficient geranylgeranylation of Ram\/Rab27 in choroideremia","volume":"270","author":"Seabra","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1172\/JCI0215058","article-title":"Functional redundancy of Rab27 proteins and the pathogenesis of Griscelli syndrome","volume":"110","author":"Barral","year":"2002","journal-title":"J. Clin. Investig."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"9195","DOI":"10.1093\/nar\/gku594","article-title":"Activity-associated miRNA are packaged in Map1b-enriched exosomes released from depolarized neurons","volume":"42","author":"Goldie","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1016\/j.cell.2009.07.051","article-title":"Trans-synaptic transmission of vesicular Wnt signals through Evi\/Wntless","volume":"139","author":"Korkut","year":"2009","journal-title":"Cell"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1016\/j.neuron.2013.01.013","article-title":"Regulation of postsynaptic retrograde signaling by presynaptic exosome release","volume":"77","author":"Korkut","year":"2013","journal-title":"Neuron"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Zhang, L., Lin, T.V., Yuan, Q., Sadoul, R., Lam, T.T., and Bordey, A. (2020). Small extracellular vesicles control dendritic spine development through regulation of HDAC2 signaling. J. Neuro Sci., in press.","DOI":"10.1523\/JNEUROSCI.0766-20.2021"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/3\/622\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:34:17Z","timestamp":1760160857000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/3\/622"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,11]]},"references-count":49,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2021,3]]}},"alternative-id":["cells10030622"],"URL":"https:\/\/doi.org\/10.3390\/cells10030622","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,11]]}}}