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Human Tyrosine Hydroxylase Gene Promoter

Imbalances in brain catecholamine (CA) neurotransmitter systems are associated with aging as well as a wide array of debilitating neurological and psychiatric disorders, including Parkinson's disease, Alzheimer's disease, Tourette's syndrome, manic-depressive illness and schizophrenia. These ailments serve to underscore the critical importance that CAs play in the proper functioning of the brain. The availability of CA neurotransmitters is largely determined by regulation of the rate-limiting enzyme, tyrosine hydroxylase (TH).

Over the past decade, we have focused on identifying the genetic and epigenetic agents that regulate the first expression of the TH gene, with the hope of discovering how to manipulate its expression. We have taken advantage of the fact that some developing neurons are phenotypically plastic for a time during embryogenesis. During this brief window, we discovered that neurons can trans-differentiate into TH-expressing and DA-producing cells if they are exposed to the synergistic interaction of specific growth factors (aFGF, bFGF, BDNF) and an obligatory co-activating molecule (such as protein kinase A and C pathway activators). We now know that one of the key pathways followed by these signals is through MAP kinase to the AP-1 site on the 5' flanking region of the TH gene. Our more recent studies have explored other important site of regulation, particularly for the human TH gene which appears to be uniquely regulated.

Our current aims are to identify: 1) the cis-and trans-activating factors involved in transcriptional regulation of the human TH gene; 2) the signal transduction pathways that lead to their activation; 3) the cellular/molecular changes that promote or inhibit expression of the human TH gene and 4) whether the differentiation of other neurotransmitter phenotypes can be similarly regulated. The long-range goal of this work is to elucidate the cellular and molecular processes regulating neurotransmitter synthesis so that brain cells or engineered stem cells can be stimulated to produce more or less of the appropriate neurotransmitters in the damaged, diseased or aging brain.

Related Publications

Romano G, Suon S, Donaldson AE, Jin H and Iacovitti L . Characterization of five evolutionary conserved regions of the human tyrosine hydroxylase (TH) promoter: implications for the engineering of a human TH minimal promoter assembled in a self-inactivating lentiviral vector system. (Submitted, J Neurochem, 2004).

Kessler MA, Yang M, Gollomp KL, Jin H, Iacovitti L . The human tyrosine hydroxylase promoter. Brain Res Mol Brain Res 2003 Apr 10;112(1-2):8-23.

Du X and Iacovitti L . Multiple signaling pathways direct the initiation of tyrosine hydroxylase gene expression in Cultured Brain neurons. Mol. Brain Res 1997;50:1-8.

Guo Z, Stull ND and Iacovitti L . Molecular mechanisms underlying the synergistic induction of tyrosine hydroxylase gene expression by acidic fibroblast growth factor and co-activators. J Neuroscience 1998;18:8163-8174.