Ultrasonic vocalization impairment of Foxp2 (R552H) knockin mice related to speech-language disorder and abnormality of Purkinje cells

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.

[1]  A. Monaco,et al.  FOXP2 expression during brain development coincides with adult sites of pathology in a severe speech and language disorder. , 2003, Brain : a journal of neurology.

[2]  Weiguo Shu,et al.  Characterization of a New Subfamily of Winged-helix/Forkhead (Fox) Genes That Are Expressed in the Lung and Act as Transcriptional Repressors* , 2001, The Journal of Biological Chemistry.

[3]  A. Monaco,et al.  A forkhead-domain gene is mutated in a severe speech and language disorder , 2001, Nature.

[4]  M. Mishkin,et al.  Language fMRI abnormalities associated with FOXP2 gene mutation , 2003, Nature Neuroscience.

[5]  H. Ino Immunohistochemical Characterization of the Orphan Nuclear Receptor RORα in the Mouse Nervous System , 2004, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[6]  Simon E. Fisher,et al.  Localisation of a gene implicated in a severe speech and language disorder , 1997, Nature Genetics.

[7]  T. Jatkoe,et al.  The G0/G1 switch gene 2 is a novel PPAR target gene. , 2005, The Biochemical journal.

[8]  M. Momoi,et al.  Absence of causative mutations and presence of autism-related allele in FOXP2 in Japanese autistic patients , 2005, Brain and Development.

[9]  Y Kouroku,et al.  ER stress (PERK/eIF2α phosphorylation) mediates the polyglutamine-induced LC3 conversion, an essential step for autophagy formation , 2007, Cell Death and Differentiation.

[10]  S. W. Davies,et al.  Exon 1 of the HD Gene with an Expanded CAG Repeat Is Sufficient to Cause a Progressive Neurological Phenotype in Transgenic Mice , 1996, Cell.

[11]  M. Mishkin,et al.  FOXP2 and the neuroanatomy of speech and language , 2005, Nature Reviews Neuroscience.

[12]  A. Monaco,et al.  Molecular evolution of FOXP2, a gene involved in speech and language , 2002, Nature.

[13]  K. Sakamaki,et al.  Polyglutamine aggregates stimulate ER stress signals and caspase-12 activation. , 2002, Human molecular genetics.

[14]  G. Marcus,et al.  FOXP2 in focus: what can genes tell us about speech and language? , 2003, Trends in Cognitive Sciences.

[15]  M. Ullman A neurocognitive perspective on language: The declarative/procedural model , 2001, Nature Reviews Neuroscience.

[16]  Shanru Li,et al.  Transcriptional and DNA Binding Activity of the Foxp1/2/4 Family Is Modulated by Heterotypic and Homotypic Protein Interactions , 2004, Molecular and Cellular Biology.

[17]  R. Margolis,et al.  FOXP2: novel exons, splice variants, and CAG repeat length stability , 2002, Human Genetics.

[18]  M. Mortrud,et al.  The G protein-coupled receptor repertoires of human and mouse , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[19]  J. Buxbaum,et al.  Altered ultrasonic vocalization in mice with a disruption in the Foxp2 gene. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[20]  K. Davies,et al.  Functional genetic analysis of mutations implicated in a human speech and language disorder. , 2006, Human molecular genetics.

[21]  Enrico Alleva,et al.  Ultrasonic vocalisation emitted by infant rodents: a tool for assessment of neurobehavioural development , 2001, Behavioural Brain Research.

[22]  Kaoru Takahashi,et al.  Expression of Foxp2, a gene involved in speech and language, in the developing and adult striatum , 2003, Journal of neuroscience research.

[23]  N. Sykes,et al.  Identification of FOXP2 truncation as a novel cause of developmental speech and language deficits. , 2005, American journal of human genetics.

[24]  Jacqueline Blundell,et al.  A Neuroligin-3 Mutation Implicated in Autism Increases Inhibitory Synaptic Transmission in Mice , 2007, Science.

[25]  Mariko Y Momoi,et al.  Intracellular distribution of a speech/language disorder associated FOXP2 mutant. , 2007, Biochemical and biophysical research communications.

[26]  R. Shigemoto,et al.  Localization of metabotropic GABA receptor subunits GABAB1 and GABAB2 relative to synaptic sites in the rat developing cerebellum , 2006, The European journal of neuroscience.

[27]  V. Beneš,et al.  Point mutation of bacterial artificial chromosomes by ET recombination , 2000, EMBO reports.

[28]  K. Chada,et al.  Expression of the helix‐loop‐helix genes Id‐1 and NSCL‐1 during cerebellar development , 1997, Developmental dynamics : an official publication of the American Association of Anatomists.

[29]  C. Scharff,et al.  FoxP2 Expression in Avian Vocal Learners and Non-Learners , 2004, The Journal of Neuroscience.

[30]  Hao Fu,et al.  Microarray analysis uncovers retinoid targets in human bronchial epithelial cells , 2003, Oncogene.