Pleiotropic effects in Eya3 knockout mice

<p>Abstract</p> <p>Background</p> <p>In <it>Drosophila</it>, mutations in the gene <it>eyes absent </it>(<it>eya</it>) lead to severe defects in eye development. The functions of its mammalian orthologs <it>Eya1-4 </it>are only partially understood and no mouse model exists for <it>Eya3</it>. Therefore, we characterized the phenotype of a new <it>Eya3 </it>knockout mouse mutant.</p> <p>Results</p> <p>Expression analysis of <it>Eya3 </it>by <it>in-situ </it>hybridizations and β-Gal-staining of <it>Eya3 </it>mutant mice revealed abundant expression of the gene throughout development, e.g. in brain, eyes, heart, somites and limbs suggesting pleiotropic effects of the mutated gene. A similar complex expression pattern was observed also in zebrafish embryos.</p> <p>The phenotype of young adult <it>Eya3 </it>mouse mutants was systematically analyzed within the German Mouse Clinic. There was no obvious defect in the eyes, ears and kidneys of <it>Eya3 </it>mutant mice. Homozygous mutants displayed decreased bone mineral content and shorter body length. In the lung, the tidal volume at rest was decreased, and electrocardiography showed increased JT- and PQ intervals as well as decreased QRS amplitude. Behavioral analysis of the mutants demonstrated a mild increase in exploratory behavior, but decreased locomotor activity and reduced muscle strength. Analysis of differential gene expression revealed 110 regulated genes in heart and brain. Using real-time PCR, we confirmed <it>Nup155 </it>being down regulated in both organs.</p> <p>Conclusion</p> <p>The loss of <it>Eya3 </it>in the mouse has no apparent effect on eye development. The wide-spread expression of <it>Eya3 </it>in mouse and zebrafish embryos is in contrast to the restricted expression pattern in <it>Xenopus </it>embryos. The loss of <it>Eya3 </it>in mice leads to a broad spectrum of minor physiological changes. Among them, the mutant mice move less than the wild-type mice and, together with the effects on respiratory, muscle and heart function, the mutation might lead to more severe effects when the mice become older. Therefore, future investigations of <it>Eya3 </it>function should focus on aging mice.</p

A Humanized Version of Foxp2 Affects Cortico-Basal Ganglia Circuits in Mice

It has been proposed that two amino acid substitutions in the transcription factor FOXP2 have been positively selected during human evolution due to effects on aspects of speech and language. Here, we introduce these substitutions into the endogenous Foxp2 gene of mice. Although these mice are generally healthy, they have qualitatively different ultrasonic vocalizations, decreased exploratory behavior and decreased dopamine concentrations in the brain suggesting that the humanized Foxp2 allele affects basal ganglia. In the striatum, a part of the basal ganglia affected in humans with a speech deficit due to a nonfunctional FOXP2 allele, we find that medium spiny neurons have increased dendrite lengths and increased synaptic plasticity. Since mice carrying one nonfunctional Foxp2 allele show opposite effects, this suggests that alterations in cortico-basal ganglia circuits might have been important for the evolution of speech and language in humans

Only half of Dutch doctors report euthanasia, report says

It has been proposed that two amino acid substitutions in the transcription factor FOXP2 have been positively selected during human evolution due to effects on aspects of speech and language. Here, we introduce these substitutions into the endogenous Foxp2 gene of mice. Although these mice are generally healthy, they have qualitatively different ultrasonic vocalizations, decreased exploratory behavior and decreased dopamine concentrations in the brain suggesting that the humanized Foxp2 allele affects basal ganglia. In the striatum, a part of the basal ganglia affected in humans with a speech deficit due to a nonfunctional FOXP2 allele, we find that medium spiny neurons have increased dendrite lengths and increased synaptic plasticity. Since mice carrying one nonfunctional Foxp2 allele show opposite effects, this suggests that alterations in cortico-basal ganglia circuits might have been important for the evolution of speech and language in humans

Requirement of the RNA-editing Enzyme ADAR2 for Normal Physiology in Mice*

ADAR2, an RNA editing enzyme that converts specific adenosines to inosines in certain pre-mRNAs, often leading to amino acid substitutions in the encoded proteins, is mainly expressed in brain. Of all ADAR2-mediated edits, a single one in the pre-mRNA of the AMPA receptor subunit GluA2 is essential for survival. Hence, early postnatal death of mice lacking ADAR2 is averted when the critical edit is engineered into both GluA2 encoding Gria2 alleles. Adar2−/−/Gria2R/R mice display normal appearance and life span, but the general phenotypic effects of global lack of ADAR2 have remained unexplored. Here we have employed the Adar2−/−/Gria2R/R mouse line, and Gria2R/R mice as controls, to study the phenotypic consequences of loss of all ADAR2-mediated edits except the critical one in GluA2. Our extended phenotypic analysis covering ∼320 parameters identified significant changes related to absence of ADAR2 in behavior, hearing ability, allergy parameters and transcript profiles of brain