Disruption of gene expression rhythms in mice lacking secretory vesicle proteins IA-2 and IA-2β
Rumery, Kyle K.
Yu, Elizabeth A.
Lambert, Christopher M.
Notkins, Abner L.
Weaver, David R.
Student AuthorsElizabeth Yu
UMass Chan AffiliationsGraduate School of Biomedical Sciences, MD/PhD Program
Department of Neurobiology
Gene Expression Regulation
Mice, Inbred C57BL
Receptor-Like Protein Tyrosine Phosphatases, Class 8
Cellular and Molecular Physiology
Neuroscience and Neurobiology
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AbstractInsulinoma-associated protein (IA)-2 and IA-2β are transmembrane proteins involved in neurotransmitter secretion. Mice with targeted disruption of both IA-2 and IA-2β (double-knockout, or DKO mice) have numerous endocrine and physiological disruptions, including disruption of circadian and diurnal rhythms. In the present study, we have assessed the impact of disruption of IA-2 and IA-2β on molecular rhythms in the brain and peripheral oscillators. We used in situ hybridization to assess molecular rhythms in the hypothalamic suprachiasmatic nuclei (SCN) of wild-type (WT) and DKO mice. The results indicate significant disruption of molecular rhythmicity in the SCN, which serves as the central pacemaker regulating circadian behavior. We also used quantitative PCR to assess gene expression rhythms in peripheral tissues of DKO, single-knockout, and WT mice. The results indicate significant attenuation of gene expression rhythms in several peripheral tissues of DKO mice but not in either single knockout. To distinguish whether this reduction in rhythmicity reflects defective oscillatory function in peripheral tissues or lack of entrainment of peripheral tissues, animals were injected with dexamethasone daily for 15 days, and then molecular rhythms were assessed throughout the day after discontinuation of injections. Dexamethasone injections improved gene expression rhythms in liver and heart of DKO mice. These results are consistent with the hypothesis that peripheral tissues of DKO mice have a functioning circadian clockwork, but rhythmicity is greatly reduced in the absence of robust, rhythmic physiological signals originating from the SCN. Thus, IA-2 and IA-2β play an important role in the regulation of circadian rhythms, likely through their participation in neurochemical communication among SCN neurons.
SourceAm J Physiol Endocrinol Metab. 2012 Sep 15;303(6):E762-76. doi: 10.1152/ajpendo.00513.2011. Epub 2012 Jul 11. Link to article on publisher's website
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/33268
Kyle Rumery participated in this study as part of the University of Massachusetts Medical School Summer Undergraduate Research Program.