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

Student Author(s)

Elizabeth Yu

Academic Program


UMMS Affiliation

Department of Neurobiology; Weaver Lab; Graduate School of Biomedical Sciences, MD/PhD Program

Publication Date


Document Type



Cellular and Molecular Physiology | Neuroscience and Neurobiology


Insulinoma-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.


UMCCTS funding

DOI of Published Version



Am 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

Journal/Book/Conference Title

American journal of physiology. Endocrinology and metabolism


Kyle Rumery participated in this study as part of the University of Massachusetts Medical School Summer Undergraduate Research Program.

Related Resources

Link to article in PubMed

PubMed ID