Control of pathogenicity and disease specificity of a T-lymphomagenic gammaretrovirus by E-box motifs but not by an overlapping glucocorticoid response element.

Although transcription factors of the basic-helix-loop-helix family have been shown to regulate enhancers of lymphomagenic gammaretroviruses through E-box motifs, overlap of an E-box motif (Egre) with the glucocorticoid response element (GRE) has obscured their function in vivo. We here report that Egre, but not the GRE affects disease induction by the murine T-lymphomagenic SL3-3 virus. Mutating all three copies of Egre prolonged the tumor latency period from 60 to 109 days. Further mutating an E-box motif (Ea/s) outside the enhancer prolonged the latency period to 180 days, suggesting that Ea/s works as a back-up site for Egre. While SL3-3 wt, GRE and Ea/s mutants induced exclusively T-cell lymphomas with wild type latencies, mainly of the CD4+CD8- phenotype, the Egre as well as the Egre plus Ea/s mutants induced B-cell lymphomas and myeloid leukemia in addition to T-cell lymphomas. T-cell lymphomas induced by the two Egre mutants had the same phenotype as those induced by SL3-3 wt, indicating incomplete disruption of T-cell lymphomagenesis in contrast to previous findings for a Runx site mutant of SL3-3. Mutating the Egre site or Egre plus Ea/s triggered several tumor phenotype-associated secondary enhancer changes encompassing neighboring sites, none of which led to regeneration of an E-box motif. Altogether, our results demonstrate a role for the E-box, but not the GRE in T-lymphomagenesis by SL3-3, unveil an inherent broader disease specificity of the virus, and strengthen the notion of selection for more potent enhancer variants of mutated viruses during tumor development

A mouse model for human-specific changes in FOXP2, a gene important for speech and language.

Comparisons of human and ape genomes generate hypotheses about the molecular basis of human-specific traits but the extent to which these hypotheses can be tested in experimental systems is currently unclear. One such hypothesis states that two human-specific amino acid changes encoded in the gene FOXP2 have been fixed by positive selection due to some effect on speech and language. We have generated a mouse model for these two amino acid changes and analyzed their effect on striatal gene expression, neuronal differentiation, electrophysiology, neuroanatomy, ultrasonic vocalizations of pups and over 240 other phenotypes. We find that the humanized FOXP2 has a significant effect on genome-wide gene expression patterns in the developing and adult striatum, leads to increased neurite outgrowth in differentiated neural precursors and increases the synaptic activity recorded from striatal medium spiny neurons. On a behavioral level, mice carrying the humanized FOXP2 explore a new environment more cautiously and vocalize at slightly lower frequencies and modulate calls differently. Our results indicate that human-specific amino acid changes in FOXP2 affected the brain and not other organs in which FOXP2 is also expressed. Furthermore, the changes in vocalization support the hypothesis that these changes affected speech and/or language while the neuronal phenotype suggests that the cellular mechanism by which this happened could have been increased neuronal connectivity. These findings open up new possibilities to study the neurological and molecular basis of human-specific properties of FOXP2 and allow guarded optimism that also other genetic changes that have been of importance during human evolution can be investigated using transgenic approaches in the mouse

The German mouse clinic: A platform for systemic phenotype analysis of mouse models

The German Mouse Clinic (GMC) is a large scale phenotyping center where mouse mutant lines are analyzed in a standardized and comprehensive way. The result is an almost complete picture of the phenotype of a mouse mutant line - a systemic view. At the GMC, expert scientists from various fields of mouse research work in close cooperation with clinicians side by side at one location. The phenotype screens comprise the following areas: allergy, behavior, clinical chemistry, cardiovascular analyses, dysmorphology, bone and cartilage, energy metabolism, eye and vision, hostpathogen interactions, immunology, lung function, molecular phenotyping, neurology, nociception, steroid metabolism, and pathology. The German Mouse Clinic is an open access platform that offers a collaboration-based phenotyping to the scientific community (www.mouseclinic.de). More than 80 mutant lines have been analyzed in a primary screen for 320 parameters, and for 95% of the mutant lines we have found new or additional phenotypes that were not associated with the mouse line before. Our data contributed to the association of mutant mouse lines to the corresponding human disease. In addition, the systemic phenotype analysis accounts for pleiotropic gene functions and refines previous phenotypic characterizations. This is an important basis for the analysis of underlying disease mechanisms. We are currently setting up a platform that will include environmental challenge tests to decipher genome-environmental interactions in the areas nutrition, exercise, air, stress and infection with different standardized experiments. This will help us to identify genetic predispositions as susceptibility factors for environmental influences