Faculty Profiles

Jimo Borjigin Assistant Professor of Physiology   Ph.D., Johns Hopkins, 1994 7629 Med Sci II (734) 763-5453   borjigin@umich.edu

The pineal gland is a neuroendocrine organ of the brain that synthesizes and releases melatonin, a nocturnal hormone important in seasonal reproduction, sleep, and pacemaker modulation. Melatonin production is controlled centrally by a biological clock in the suprachiasmatic nucleus (SCN) in the form of nightly norepinephrine release, and is the most reliable marker of the central pacemaker. Locally within the pineal gland, melatonin production is dictated by the combined action of cAMP signaling and pineal specific transcriptional activities.

The first focus of my lab is to investigate the properties of the central pacemaker by studying the melatonin output, the hands of the circadian clock under normal and perturbed conditions. To facilitate analysis of the central pacemaker, we have recently developed a long-term automated pineal microdialysis technique, which allows us to follow melatonin secretion from individual animals for long time with precision and high temporal resolution. Using this new approach, we have found some interesting features of the central pacemaker that have not been appreciated. We plan to investigate in detail the properties of entrainment of the circadian clock following light stimulation of various kinds.

The second focus of my lab is to study how circadian rhythms of a key melatonin synthetic enzyme N-acetyltransferase (NAT) is regulated at transcriptional levels within the pineal gland. Our studies have demonstrated that cAMP signaling is both necessary and sufficient for induction of NAT transcription and melatonin formation in vivo. We have also found that Crx, a pineal and retina specific transcription factor, appears to be important in pineal NAT expression. Our plan is to study the temporal and spatial regulation of circadian NAT transcription with an emphasis on identification of the key in vivo factors mediating the cAMP responses and players controlling pineal specific NAT transcription and melatonin formation.

The third area of our research is focused on the role of PINA (Pineal Night specific ATPase, a novel variant of copper-transporting ATP7B that is defective in Wilson Disease) in circadian rhythm and Wilson disease. In the past few years, we have performed detailed molecular and physiological analysis of PINA mutant rats and concluded that PINA function is independent of melatonin formation. This discovery leads to an exciting possibility that the pineal may have novel circadian functions that require PINA. We will attempt to identify and isolate molecules that may be the product of PINA activity in the night pineal using a combination of molecular and biochemical techniques. Ultimately, we will manipulate these molecules in the intact animal to determine their physiological effects using real-time microdialysis.

key words: circadian rhythms, biological clock, suprachiasmatic nucleus (SCN), pineal gland, melatonin, cAMP signaling, homeobox transcription factors, transcriptional synergy, Pineal Night specific ATPase, Wilson Disease

Borjigin J, Wang MM, Snyder SH."Diurnal Variation in mRNA Encoding Serotonin N-acetyltransferase in Pineal Gland.", Nature. 1995 Dec 21-28; 378(6559):783-5.

Li X, Chen S, Wang Q, Zack DJ, Snyder SH, Borjigin J. "A Pineal Regulatory Element (PIRE) Mediates Transactivation by the Pineal/Retina-Specific Transcription Factor CRX.", Proc Natl Acad Sci USA. 1998 Feb 17; 95(4):1876-81.

Borjigin J, Payne AS, Deng J, Li X, Wang MM, Ovodenko B, Gitlin JD, Snyder SH. "A Novel Pineal Night-Specific ATPase Encoded by the Wilson Disease Gene.", J Neurosci. 1999 Feb 1; 19(3): 1018-26.

Sun X, Deng J, Liu T, Borjigin J. "Circadian 5-HT Production Regulated by Adrenergic Signaling.", Proc Natl Acad Sci USA. 2002 Apr 2; 99(7):4686-91.

Borjigin J, Deng J, Sun X, De Jesus M, Liu T, Wang MM. "Diurnal Pineal 3-O-Sulphotransferase 2 Expression Controlled by Beta-Adrenergic Repression.", J Biol Chem. 2003 May 2; 278(18):16315-9.

Sun X, Liu T, Deng J, Borjigin J. "Long-term In Vivo Pineal Microdialysis.", J Pineal Res. 2003 Sep; 35(2):118-24.

Ahmed S, Deng J, Borjigin J, "A New Strain of Rat for Functional Analysis of PINA", (2005), Molecular Brain Researc, 137(1-2):63-9.

Huang ZP, Deng J, Borjigin J, "A Novel H28Y Mutation in LEC Rats Leads to Decreased NAT Protein Stability In Vivo and In Vitro", (2005), J. Pineal Res., 39(1):84-90.

Liu T, Borjigin J, "NAT is not the Rate-Limiting Enzyme of Melatonin Synthesis at Night", (2005), J. Pineal Res., 39(1):91-6.

Liu T, Borjigin J, "Free Running Rhythms of Pineal Circadian Output", (2005), J. Biol. Rhythms, 20(5):430-440.

Liu T, Borjigin J, "Reentrainment of the Circadian Pacemaker Through 3 Distinct Stages", (2005), J. Biol. Rhythms, 20(5):441-450.

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