UC San Diego

Nuclear hormone receptors influence transcription in reproduction, development, and adult physiology by associating with hormones and metabolic intermediates, or in the case of orphan receptors, by acting independently of endocrine or metabolic ligands. A critical role for the orphan receptor, Estrogen-Related Receptor [gamma]; (ERR[gamma]) is indicated by a lack of feeding and neonatal death (>72 hours after birth) of mice deficient in this transcription factor. Analysis of motor function in whole animal or in reduced preparations reveals a significant defect in ERR[gamma]-null animals. Electrophysiologic analysis of isolated lumbar spinal cords has demonstrated an increase in spontaneous activity and a defect in the central pattern generating circuits. ERR[gamma] is robustly expressed in the heart from early development (E8.5) through adulthood. Electrocardiographic analysis of ERR[gamma]-null and heterozygous animals reveals a prolongation of the QRS complex, ST and QT intervals. Isolated primary cardiomyocytes from E18.5 animals display a significant reduction in sodium current, consistent with observed ECG abnormalities. Several ion channels are dysregulated in E18.5 heart, by QPCR. Additionally, derangements of mitochondrial genes have been detected by expression and chromatin IP (ChIP) array analyses. Mitochondrial DNA is increased, per ventricular heart cell, in the ERRγ-nulls and ERR[gamma]- nulls are prone to fasting-induced lactic acidosis. These signs of mitochondrial dysfunction occur despite normal substrate utilization, electron transport chain protein levels, and electron micrographic morphology. ERR[gamma] appears to define the metabolic state of these excitable tissues--loss of which results in subtle, yet lethal alterations in the firing properties of these neurons. Ongoing studies are to define the characteristics of ERR[gamma]-positive cells in the spinal cord, and to determine the contribution of ERR[gamma] to the normal function of excitable cells in the heart and lumbar spinal cord