The serotonergic neurons of the raphe nuclei are the primary site of serotonin synthesis in the brain. They send projections to a wide variety of brain regions, including the hippocampus, cortex, limbic system, and hypothalamus (1). Activation of postsynaptic receptors in the above regions is associated with serotonergic regulation of memory, motivation, emotion, neuroendocrine stress response, etc. (2-4). The activity of serotonergic neurons of the raphe nuclei is regulated in part by presynaptic autoreceptors. The 5-HT1A autoreceptor is located at the cell body and dendrites of raphe serotonergic neurons (5, 6) and mediates negative feedback inhibition of the firing rate through recurrent activation of potassium channels via pertussis toxin-sensitive G proteins (7) to decrease serotonin release. Thus the 5-HT1A receptor plays a major role in controlling serotonergic outflow to the wide variety of brain regions that are innervated by the raphe nuclei.Abnormal regulation of 5-HT1A receptor expression is implicated in depression and anxiety disorders. 5-HT1A receptor knockout mice display increased anxiety-related behaviors (8 -10), suggesting that a loss of the 5-HT1A autoreceptors is correlated with symptoms of anxiety (3). On the other hand, 5-HT1A receptor levels are increased in the midbrain of suicide victims with major depression compared with nondepressed suicides (11). Down-regulation of the 5-HT1A autoreceptor by antidepressants (12, 13) disinhibits action potential firing of the raphe neuron, thereby enhancing serotonergic neurotransmission (14 -17). The prolonged (2-3 week) time course required for antidepressant action suggests an alteration in transcriptional activity of the 5-HT1A receptor.To investigate the mechanisms that regulate cell-specific and basal regulation of the 5-HT1A receptor, we have identified the transcriptional start site and examined the regulation of the transcriptional activity of a 2.719-kb 1 fragment of the rat 5-HT1A receptor gene in several cell lines, including 5-HT1A receptor-positive RN46A raphe and SN48 septal cells (18 -20) and receptor-negative L6 myoblast and C6 glioblastoma cells (21). We identified a region of the rat 5-HT1A receptor gene located upstream of an ubiquitously active promoter region that reduces transcriptional activity. In the present study, we have identified a 14-bp element in the 5Ј-flanking region of the 5-HT1A gene that mediates transcriptional repression in raphe cells, but is dispensable in receptor-negative cells where an adjacent 12-bp element maintains repression of the gene. In contrast to the single repressor-DNA complex present in 5-HT1A receptor-expressing cells that may modulate basal levels of receptor expression, the presence of two protein-DNA complexes in receptor-negative cell lines provides a dual mechanism to repress 5-HT1A receptor expression.

These results clarify the molecular mechanism underlying up-regulation of Wnt-5A by IL-1β in chondrocytes, suggesting an important functional crosstalk between Wnt-5A and NF-κB signaling pathways. This finding provides new insights into the involvement of Wnt signaling in the cartilage destruction caused by arthritis.

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This study provides a new gene expression profile of the progression of OA. Further study of these OA-related genes may provide new insights into understanding the molecular mechanisms underlying OA.

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