title: De novo inbred heterozygous Zeb2/Sip1 mutant mice uniquely generated by germ-line conditional knockout exhibit craniofacial, callosal and behavioral defects associated with Mowat-Wilson syndrome.
abstract: Mowat-Wilson syndrome (MOWS) is caused by de novo heterozygous mutation at ZEB2 (SIP1, ZFHX1B) gene, and exhibit moderate to severe intellectual disability (ID), a characteristic facial appearance, epilepsy and other congenital anomalies. Establishing a murine MOWS model is important, not only for investigating the pathogenesis of this disease, but also for identifying compounds that may improve the symptoms. However, because the heterozygous Zeb2 knockout mouse could not be maintained as a mouse line with the inbred C57BL/6 background, it was difficult to use those mice for the study of MOWS. Here, we systematically generated de novo Zeb2 Δex7/+ mice by inducing the Zeb2 mutation in the germ cells using conditional recombination system. The de novo Zeb2 Δex7/+ mice with C57BL/6 background developed multiple defects relevant to MOWS, including craniofacial abnormalities, defective corpus callosum formation and the decreased number of parvalbumin interneurons in the cortex. In behavioral analyses, these mice showed reduced motor activity, increased anxiety and impaired sociability. Notably, during the Barnes maze test, immobile Zeb2 mutant mice were observed over repeated trials. In contrast, neither the mouse line nor the de novo Zeb2 Δex7/+ mice with the closed colony ICR background showed cranial abnormalities or reduced motor activities. These results demonstrate the advantages of using de novo Zeb2 Δex7/+ mice with the C57BL/6 background as the MOWS model. To our knowledge, this is the first time an inducible de novo mutation system has been applied to murine germline cells to produce an animal model of a human congenital disease.
authors: Department of Perinatology, Institute for Developmental Research, Aichi Human Service Center, 713-8 Kagiya-cho, Kasugai, Aichi 480-0392, Japan.
authors: Tsuyoshi
authors: T
authors: Takagi
authors: Department of Perinatology, Institute for Developmental Research, Aichi Human Service Center, 713-8 Kagiya-cho, Kasugai, Aichi 480-0392, Japan.
authors: Yuriko
authors: Y
authors: Nishizaki
authors: Department of Perinatology, Institute for Developmental Research, Aichi Human Service Center, 713-8 Kagiya-cho, Kasugai, Aichi 480-0392, Japan.
authors: Fumiko
authors: F
authors: Matsui
authors: Department of Genetics, Institute for Developmental Research, Aichi Human Service Center, 713-8 Kagiya-cho, Kasugai, Aichi 480-0392, Japan.
authors: Nobuaki
authors: N
authors: Wakamatsu
authors: Department of Perinatology, Institute for Developmental Research, Aichi Human Service Center, 713-8 Kagiya-cho, Kasugai, Aichi 480-0392, Japan higashi@inst-hsc.jp.
authors: Yujiro
authors: Y
authors: Higashi
mesh_terms: D058540:Aicardi Syndrome / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism; D019465:Craniofacial Abnormalities / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004827:Epilepsy / Q000235:genetics / Q000378:metabolism; D019066:Facies; D005260:Female; D056726:Genetic Association Studies; D005854:Germ Cells; D018095:Germ-Line Mutation; D006579:Heterozygote; D006627:Hirschsprung Disease / Q000235:genetics* / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000378:metabolism; D008297:Male; D001523:Mental Disorders / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D008831:Microcephaly / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism*; D000074165:Zinc Finger E-box Binding Homeobox 2
chemical_list: D018398:Homeodomain Proteins; D012097:Repressor Proteins; C120602:ZEB2 protein, mouse; D000074165:Zinc Finger E-box Binding Homeobox 2