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Analysis of compound heterozygotes reveals that the mouse floxed Pax6 (tm1Ued) allele produces abnormal eye phenotypes.

ABSTRACT: Analysis of abnormal phenotypes produced by different types of mutations has been crucial for our understanding of gene function. Some floxed alleles that retain a neomycin-resistance selection cassette (neo cassette) are not equivalent to wild-type alleles and provide useful experimental resources. Pax6 is an important developmental gene and the aim of this study was to determine whether the floxed Pax6 (tm1Ued) (Pax6 (fl) ) allele, which has a retained neo cassette, produced any abnormal eye phenotypes that would imply that it differs from the wild-type allele. Homozygous Pax6 (fl/fl) and heterozygous Pax6 (fl/+) mice had no overt qualitative eye abnormalities but morphometric analysis showed that Pax6 (fl/fl) corneas tended be thicker and smaller in diameter. To aid identification of weak effects, we produced compound heterozygotes with the Pax6 (Sey-Neu) (Pax6 (-)) null allele. Pax6 (fl/-) compound heterozygotes had more severe eye abnormalities than Pax6 (+/-) heterozygotes, implying that Pax6 (fl) differs from the wild-type Pax6 (+) allele. Immunohistochemistry showed that the Pax6 (fl/-) corneal epithelium was positive for keratin 19 and negative for keratin 12, indicating that it was abnormally differentiated. This Pax6 (fl) allele provides a useful addition to the existing Pax6 allelic series and this study demonstrates the utility of using compound heterozygotes with null alleles to unmask cryptic effects of floxed alleles.

SUBMITTER: Dora NJ

PROVIDER: S-EPMC5023747 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Analysis of compound heterozygotes reveals that the mouse floxed Pax6 (tm1Ued) allele produces abnormal eye phenotypes.

Dorà Natalie J NJ Crookshanks Aaron J F AJ Leung Karen K Y KK Simpson T Ian TI Mason John O JO Price David J DJ West John D JD

Transgenic research 20160530 5

Analysis of abnormal phenotypes produced by different types of mutations has been crucial for our understanding of gene function. Some floxed alleles that retain a neomycin-resistance selection cassette (neo cassette) are not equivalent to wild-type alleles and provide useful experimental resources. Pax6 is an important developmental gene and the aim of this study was to determine whether the floxed Pax6 (tm1Ued) (Pax6 (fl) ) allele, which has a retained neo cassette, produced any abnormal eye p ...[more]

PMID: 27240603

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Project description:BackgroundAngelman Syndrome (AS) is a rare genetic disorder characterized by impaired communication, motor and balance deficits, intellectual disabilities, recurring seizures and abnormal sleep patterns. The genetic cause of AS is neuronal-specific loss of expression of UBE3A (ubiquitin-protein ligase E6-AP), an imprinted gene. Seizure and sleep disorders are highly prevalent (> 80%) in the AS population. The present experiments were designed to identify translational, neurophysiological outcome measures in a model of AS.MethodsWe used the exon-2 deletion mouse (Ube3a-del) on a C57BL/6J background to assess seizure, sleep and electrophysiological phenotypes. Seizure susceptibility has been reported in Ube3a-del mice with a variety of seizure induction methods. Here, we provoked seizures by a single high-dose injection of 80 mg/kg pentylenetetrazole. Novel experiments included the utilization of wireless telemetry devices to acquire global electroencephalogram (EEG) and neurophysiological data on electrographic seizures, power spectra, light-dark cycles, sleep stages and sleep spindles in Ube3a-del and WT mice.ResultsUbe3a-del mice exhibited reduced seizure threshold compared to WT. EEG illustrated that Ube3a-del mice had increased epileptiform spiking activity and delta power, which corroborates findings from other laboratories and recapitulates clinical reports in AS. This is the first report to use a cortical surface-based recording by a wireless telemetry device over tethered/fixed head-mount depth recordings. Less time in both paradoxical and slow-wave sleep, longer latencies to paradoxical sleep stages and total less sleep time in Ube3a-del mice were observed compared to WT. For the first time, we detected fewer sleep spindles in the AS mouse model.LimitationsThis study was limited to the exon 2 deletion mouse model, and future work will investigate the rat model of AS, containing a complete Ube3a deletion and pair EEG with behavior.ConclusionsOur data enhance rigor and translatability as our study provides important corroboration of previous reports on epileptiform and elevated delta power. For the first time we report neurophysiological phenotypes collected via translational methodology. Furthermore, this is the first report of reduced sleep spindles, a critical marker of memory consolidation during sleep, in an AS model. Our results are useful outcomes for therapeutic testing.

Dataset Information

Analysis of compound heterozygotes reveals that the mouse floxed Pax6 (tm1Ued) allele produces abnormal eye phenotypes.

Publications

Analysis of compound heterozygotes reveals that the mouse floxed Pax6 (tm1Ued) allele produces abnormal eye phenotypes.

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