Microphthalmia, parkinsonism, and enhanced nociception in Pitx3 416insG mice
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A new spontaneous mouse mutant was characterized by closed eyelids at weaning and without apparent eyes (provisional gene name, eyeless; provisional gene symbol, eyl). The mutation follows a recessive pattern of inheritance and was mapped to the region of chromosome 19 containing Pitx3. Genetic complementation tests using Pitx3 ak/+ mice confirmed eyl as a new allele of Pitx3 (Pitx3 eyl ). Sequencing of the Pitx3 gene in eyl mutants identified an inserted G after cDNA position 416 (416insG; exon 4). The shifted open reading frame is predicted to result in a hybrid protein still containing the Pitx3 homeobox, but followed by 121 new amino acids. The novel Pitx3 eyl/eyl mutants expressed ophthalmological and brain defects similar to Pitx3 ak/ak mice: microphthalmia or anophthalmia and loss of dopamine neurons of the substantia nigra. In addition, we observed in the homozygous eyeless mutants increased extramedullary hematopoiesis in the spleen, frequently liver steatosis, and reduced body weight. There were also several behavioral changes in the homozygous mutants, including reduced forelimb grip strength and increased nociception. In addition to these alterations in both sexes, we observed in female Pitx3 eyl/eyl mice increased anxiety-related behavior, reduced locomotor activity, reduced object exploration, and increased social contacts; however, we observed decreased anxiety-related behavior and increased arousal in males. Most of these defects identified in the new Pitx3 mutation are observed in Parkinson patients, making the Pitx3 eyl mutant a valuable new model. It is the first mouse mutant carrying a point mutation within the coding region of Pitx3.
This work was supported at least in part by the German National Genome Research Network (NGFN; grants 01GS0850, 01GS0851, 01GS0852, 01GS0854, 01GS0869, 01GS0853, 01GS08156, 01GR0430, 01GR0434, 01GR0438, 01KW9948, and R0313435B), the Deutsche Forschungsgemeinschaft (FOR926), and the European Union (FP6, EUMODIC, LSHG-CT-2006-037188). The expert technical assistance of Miriam Backs, Erika Bürkle, Christine Führmann, Anita Hellemons, Elfi Holupirek, Regina Kneuttinger, Maria Kugler, Astrid Markert, Jacqueline Müller, Eleonore Samson, Bahar Sanli-Bonazzi, Sandra Schädler, Florian Schleicher, Daniela Schmid, Ann-Elisabeth Schwarz, Reinhard Seeliger, Monika Stadler, Susanne Wittich, and Claudia Zeller is gratefully acknowledged.
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