Analyses of Conditional Knockout Mice for Pogz, a Gene Responsible for Neurodevelopmental Disorders in Excitatory and Inhibitory Neurons in the Brain

Analyses of Conditional Knockout Mice for Pogz, a Gene Responsible for Neurodevelopmental Disorders in Excitatory and Inhibitory Neurons in the Brain Nanako Hamada Department of Molecular Neurobiology, Institute for Developmental Research, Aichi Developmental Disability Center, 713-8 Kamiya, Kasugai 480-0392, Japan Takuma Nishijo Department of Molecular Neurobiology, Institute for Developmental Research, Aichi Developmental Disability Center, 713-8 Kamiya, Kasugai 480-0392, Japan Ikuko Iwamoto Department of Molecular Neurobiology, Institute for Developmental Research, Aichi Developmental Disability Center, 713-8 Kamiya, Kasugai 480-0392, Japan Sagiv Shifman Department of Genetics, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel http://orcid.org/0000-0003-4071-5361 Koh-ichi Nagata Department of Molecular Neurobiology, Institute for Developmental Research, Aichi Developmental Disability Center, 713-8 Kamiya, Kasugai 480-0392, Japan Department of Neurochemistry, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan http://orcid.org/0000-0002-6827-8434

POGZ (Pogo transposable element derived with ZNF domain) is known to function as a regulator of gene expression. While variations in the POGZ gene have been associated with intellectual disabilities and developmental delays in humans, the exact pathophysiological mechanisms remain unclear. To shed light on this, we created two lines of conditional knockout mice for Pogz, one specific to excitatory neurons (Emx1-Pogz mice) and the other to inhibitory neurons (Gad2-Pogz mice) in the brain. Emx1-Pogz mice showed a decrease in body weight, similar to total Pogz knockout mice. Although the two lines did not display significant morphological abnormalities in the telencephalon, impaired POGZ function affected the electrophysiological properties of both excitatory and inhibitory neurons differently. These findings suggest that these mouse lines could be useful tools for clarifying the precise pathophysiological mechanisms of neurodevelopmental disorders associated with POGZ gene abnormalities.
03 19 2024 540 cells13060540 Japan Society for the Promotion of Science http://dx.doi.org/10.13039/501100001691 JP22H03049 JP20K21589 JP19K07059 https://creativecommons.org/licenses/by/4.0/ 10.3390/cells13060540 https://www.mdpi.com/2073-4409/13/6/540 https://www.mdpi.com/2073-4409/13/6/540/pdf Nozawa Human POGZ Modulates Dissociation of HP1α from Mitotic Chromosome Arms through Aurora B Activation Nat. Cell Biol. 2010 10.1038/ncb2075 12 719 Bartholomeeusen Lens Epithelium-Derived Growth Factor/P75 Interacts with the Transposase-Derived DDE Domain of PogZ J. Biol. Chem. 2009 10.1074/jbc.M807781200 284 11467 Ibaraki Expression Analyses of POGZ, a Responsible Gene for Neurodevelopmental Disorders, during Mouse Brain Development Dev. Neurosci. 2019 10.1159/000502128 41 139 Batzir Phenotypic Expansion of POGZ-related Intellectual Disability Syndrome (White-Sutton Syndrome) Am. J. Med. Genet. Part A 2020 10.1002/ajmg.a.61380 182 38 Stessman Disruption of POGZ Is Associated with Intellectual Disability and Autism Spectrum Disorders Am. J. Hum. Genet. 2016 10.1016/j.ajhg.2016.02.004 98 541 10.1186/s12887-023-03972-9 Duan, J., Ye, Y., Liao, J., Chen, L., Zhao, X., Liu, C., and Wen, J. (2023). White-Sutton Syndrome and Congenital Heart Disease: Case Report and Literature Review. BMC Pediatr., 23. White POGZ Truncating Alleles Cause Syndromic Intellectual Disability Genome Med. 2016 10.1186/s13073-015-0253-0 8 3 10.1007/s00246-022-03094-6 Duran, S., Gerber, C., Bilsky, S., Plummer, S., and Bocks, M. (2023). Use of Rivaroxaban in Children with Congenital Heart Disease: A Single-Center Case Series. Pediatr. Cardiol., on line ahead of print. Title Pogz Deficiency Leads to Transcription Dysregulation and Impaired Cerebellar Activity Underlying Autism-like Behavior in Mice Nat. Commun. 2020 10.1038/s41467-020-19577-0 11 5836 Matsumura Pathogenic POGZ Mutation Causes Impaired Cortical Development and Reversible Autism-like Phenotypes Nat. Commun. 2020 10.1038/s41467-020-14697-z 11 859 Gudmundsdottir POGZ Is Required for Silencing Mouse Embryonic β-like Hemoglobin and Human Fetal Hemoglobin Expression Cell Rep. 2018 10.1016/j.celrep.2018.05.043 23 3236 Taniguchi A Resource of Cre Driver Lines for Genetic Targeting of GABAergic Neurons in Cerebral Cortex Neuron 2011 10.1016/j.neuron.2011.07.026 71 995 Inaguma Sensitive Immunoassay for Rat Parvalbumin: Tissue Distribution and Developmental Changes Biochim. Biophys. Acta (BBA) Gen. Subj. 1991 10.1016/0304-4165(91)90076-S 1075 68 Tabata Efficient in Utero Gene Transfer System to the Developing Mouse Brain Using Electroporation: Visualization of Neuronal Migration in the Developing Cortex Neuroscience 2001 10.1016/S0306-4522(01)00016-1 103 865 Kawai Effect of Three Types of Mixed Anesthetic Agents Alternate to Ketamine in Mice Exp. Anim. 2011 10.1538/expanim.60.481 60 481 Nishijo Serotonin 5-HT1B Receptor-mediated Calcium Influx-independent Presynaptic Inhibition of GABA Release onto Rat Basal Forebrain Cholinergic Neurons Eur. J. Neurosci. 2016 10.1111/ejn.13273 44 1747 Lu Identification of Genes Associated with Cortical Malformation Using a Transposon-Mediated Somatic Mutagenesis Screen in Mice Nat. Commun. 2018 10.1038/s41467-018-04880-8 9 2498 Williams A Convergent Mechanism of High Risk Factors ADNP and POGZ in Neurodevelopmental Disorders Brain 2022 10.1093/brain/awac152 145 3250 Qin Social Deficits in Shank3-Deficient Mouse Models of Autism Are Rescued by Histone Deacetylase (HDAC) Inhibition Nat. Neurosci. 2018 10.1038/s41593-018-0110-8 21 564 Wang Autism Risk Gene KMT5B Deficiency in Prefrontal Cortex Induces Synaptic Dysfunction and Social Deficits via Alterations of DNA Repair and Gene Transcription Neuropsychopharmacology 2021 10.1038/s41386-021-01029-y 46 1617 Voineagu Transcriptomic Analysis of Autistic Brain Reveals Convergent Molecular Pathology Nature 2011 10.1038/nature10110 474 380 Binyameen Autism Risk Gene POGZ Promotes Chromatin Accessibility and Expression of Clustered Synaptic Genes Cell Rep. 2021 10.1016/j.celrep.2021.110089 37 110089 Tian Aurora B-Dependent Phosphorylation of Ataxin-10 Promotes the Interaction between Ataxin-10 and Plk1 in Cytokinesis Sci. Rep. 2015 10.1038/srep08360 5 8360