title: Ultrasonic vocalization impairment of Foxp2 (R552H) knockin mice related to speech-language disorder and abnormality of Purkinje cells.
abstract: Previous studies have demonstrated that mutation in the forkhead domain of the forkhead box P2 (FOXP2) protein (R553H) causes speech-language disorders. To further analyze FOXP2 function in speech learning, we generated a knockin (KI) mouse for Foxp2 (R552H) [Foxp2 (R552H)-KI], corresponding to the human FOXP2 (R553H) mutation, by homologous recombination. Homozygous Foxp2 (R552H)-KI mice showed reduced weight, immature development of the cerebellum with incompletely folded folia, Purkinje cells with poor dendritic arbors and less synaptophysin immunoreactivity, and achieved crisis stage for survival 3 weeks after birth. At postnatal day 10, these mice also showed severe ultrasonic vocalization (USV) and motor impairment, whereas the heterozygous Foxp2 (R552H)-KI mice exhibited modest impairments. Similar to the wild-type protein, Foxp2 (R552H) localized in the nuclei of the Purkinje cells and the thalamus, striatum, cortex, and hippocampus (CA1) neurons of the homozygous Foxp2 (R552H)-KI mice (postnatal day 10), and some of the neurons showed nuclear aggregates of Foxp2 (R552H). In addition to the immature development of the cerebellum, Foxp2 (R552H) nuclear aggregates may further compromise the function of the Purkinje cells and cerebral neurons of the homozygous mice, resulting in their death. In contrast, heterozygous Foxp2 (R552H)-KI mice, which showed modest impairment of USVs with different USV qualities and which did not exhibit nuclear aggregates, should provide insights into the common molecular mechanisms between the mouse USV and human speech learning and the relationship between the USV and motor neural systems.
authors.affiliation: Divisions of Development and Differentiation, Department of Human Inherited Metabolic Disease, National Institute of Neuroscience, 4-1-1 Ogawahigashi-machi, Kodaira, Tokyo 187-8502, Japan.
authors.forename: Eriko
authors.initials: E
authors.lastname: Fujita
authors.forename: Yuko
authors.initials: Y
authors.lastname: Tanabe
authors.forename: Akira
authors.initials: A
authors.lastname: Shiota
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Ueda
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Suwa
authors.forename: Mariko Y
authors.initials: MY
authors.lastname: Momoi
authors.forename: Takashi
authors.initials: T
authors.lastname: Momoi
mesh_terms: D000818:Animals; D002531:Cerebellum / Q000254:growth & development; D017931:DNA Primers / Q000235:genetics; D051858:Forkhead Transcription Factors / Q000235:genetics*; D005838:Genotype; D006651:Histocytochemistry; D007806:Language Disorders / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D046228:Microarray Analysis; D020125:Mutation, Missense / Q000235:genetics; D011689:Purkinje Cells / Q000166:cytology*; D012097:Repressor Proteins / Q000235:genetics*; D014465:Ultrasonics; D014828:Vocalization, Animal
chemical_list: D017931:DNA Primers; D051858:Forkhead Transcription Factors; C432918:Foxp2 protein, mouse; D012097:Repressor Proteins