{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T07:34:53Z","timestamp":1793432093758,"version":"4.5.0"},"reference-count":25,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,7,19]],"date-time":"2017-07-19T00:00:00Z","timestamp":1500422400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,7,19]],"date-time":"2017-07-19T00:00:00Z","timestamp":1500422400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Mutations in the X-linked gene <jats:italic>Protocadherin-19<\/jats:italic> (<jats:italic>Pcdh19<\/jats:italic>) cause female-limited epilepsy and mental retardation in humans. Although Pcdh19 is known to be a homophilic cell-cell adhesion molecule, how its mutations bring about female-specific disorders remains elusive. Here, we report the effects of <jats:italic>Pcdh19<\/jats:italic> knockout in mice on their development and behavior. <jats:italic>Pcdh19<\/jats:italic> was expressed in various brain regions including the cerebral cortex and hippocampus. Although Pcdh19-positive cells were evenly distributed in layer V of wild-type cortices, their distribution became a mosaic in <jats:italic>Pcdh19<\/jats:italic> heterozygous female cortices. In cortical and hippocampal neurons, Pcdh19 was localized along their dendrites, showing occasional accumulation on synapses. <jats:italic>Pcdh19<\/jats:italic> mutants, however, displayed no detectable abnormalities in dendrite and spine morphology of layer V neurons. Nevertheless, <jats:italic>Pcdh19<\/jats:italic> hemizygous males and heterozygous females showed impaired behaviors including activity defects under stress conditions. Notably, only heterozygous females exhibited decreased fear responses. In addition, Pcdh19 overexpression in wild-type cortices led to ectopic clustering of Pcdh19-positive neurons. These results suggest that Pcdh19 is required for behavioral control in mice, but its genetic loss differentially affects the male and female behavior, as seen in human, and they also support the hypothesis that the mosaic expression of <jats:italic>Pcdh19<\/jats:italic> in brains perturbs neuronal interactions.<\/jats:p>","DOI":"10.1038\/s41598-017-06374-x","type":"journal-article","created":{"date-parts":[[2017,7,13]],"date-time":"2017-07-13T08:15:10Z","timestamp":1499933710000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":56,"title":["Loss of X-linked Protocadherin-19 differentially affects the behavior of heterozygous female and hemizygous male mice"],"prefix":"10.1038","volume":"7","author":[{"given":"Shuichi","family":"Hayashi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoko","family":"Inoue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoko","family":"Hattori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mari","family":"Kaneko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Go","family":"Shioi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0137-8200","authenticated-orcid":false,"given":"Tsuyoshi","family":"Miyakawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9931-3378","authenticated-orcid":false,"given":"Masatoshi","family":"Takeichi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,7,19]]},"reference":[{"key":"6374_CR1","doi-asserted-by":"publisher","first-page":"406","DOI":"10.1016\/S1474-4422(13)70011-5","volume":"12","author":"A Moreno-De-Luca","year":"2013","unstructured":"Moreno-De-Luca, A. et al. Developmental brain dysfunction: revival and expansion of old concepts based on new genetic evidence. Lancet Neurol. \n                           12, 406\u2013414 (2013).","journal-title":"Lancet Neurol."},{"key":"6374_CR2","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1016\/j.biocel.2008.09.027","volume":"41","author":"P Hulpiau","year":"2009","unstructured":"Hulpiau, P. & van Roy, F. Molecular evolution of the cadherin superfamily. Int. J. Biochem. Cell Biol. \n                           41, 349\u2013369 (2009).","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"6374_CR3","doi-asserted-by":"publisher","first-page":"1455","DOI":"10.1242\/jcs.166306","volume":"128","author":"S Hayashi","year":"2015","unstructured":"Hayashi, S. & Takeichi, M. Emerging roles of protocadherins: from self-avoidance to enhancement of motility. J. Cell Sci. \n                           128, 1455\u20131464 (2015).","journal-title":"J. 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