Disruption of gene expression rhythms in mice lacking secretory vesicle proteins IA-2 and IA-2 beta

作者：Punia Sohan; Rumery Kyle K; Yu Elizabeth A; Lambert Christopher M; Notkins Abner L; Weaver David R^*

来源：American Journal of Physiology - Endocrinology And Metabolism, 2012, 303(6): E762-E776.

• circadian
• suprachiasmatic nucleus
• vasoactive intestinal peptide
• Prprn
• Ptprn2

Punia S, Rumery KK, Yu EA, Lambert CM, Notkins AL, Weaver DR. Disruption of gene expression rhythms in mice lacking secretory vesicle proteins IA-2 and IA-2 beta. Am J Physiol Endocrinol Metab 303: E762-E776, 2012. First published July 11, 2012; doi:10.1152/ajpendo.00513.2011.-Insulinoma-associated protein (IA)-2 and IA-2 beta are transmembrane proteins involved in neurotransmitter secretion. Mice with targeted disruption of both IA-2 and IA-2 beta (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-2 beta 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-2 beta play an important role in the regulation of circadian rhythms, likely through their participation in neurochemical communication among SCN neurons.

• 出版日期2012-9