Regulation of Temporal and Spatial Gene Expression in the Circadian System

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Our Unit is interested in the molecular mechanisms underlying regulated patterns of gene expression, both in time and space. Our model systems include the rodent retina and the suprachiasmatic nucleus (SCN), which contain self-sustaining molecular clocks, and the pineal gland, a slave oscillator in rodents. Currently, the program is mainly focused on the use of the Arylalkylamine N-acetyltransferase (AA-NAT) gene as a model for tissue and time of day specific gene expression. This gene encodes the key regulated enzyme in the melatonin biosynthetic pathway. Because AA-NAT is expressed in both the pineal and retina, it represents a single rhythmic output of two different kinds of oscillators. Rat and mouse transgenic technology and transient transfections of primary retinal/pineal cultures are being used to probe the different regions and elements that contribute to the observed patterns of gene expression in both systems. Accomplishments during this period: 1) The establishment of several rat transgenic lines in which an AA-NAT promoter fragment can drive proper temporal (nocturnal) and spatial (pineal/retinal) pattern of reporter gene expression. Collaborating Units: David Carter, Walles, UK; David Klein, NICHD. 2) DNA affinity purification and microsequencing of a retina factor which can bind to the photoreceptor conserved element (PCE) present in the regulatory region of the AA-NAT promoter. Surprisingly, this protein is a member of the CC(AT rich)GG (CArG) family of transcription factors. This finding could shed new light on the nature of the PCE and its possible mechanisms of action. Collaborating unit: Howard Jaffe, NINDS.