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The Journal of Neuroscience, September 1, 1998, 18(17):6631-6640

Authentic Cell-Specific and Developmentally Regulated Expression of Pro-Opiomelanocortin Genomic Fragments in Hypothalamic and Hindbrain Neurons of Transgenic Mice

Juan I. Young¹, Verónica Otero¹, Marcelo G. Cerdán¹, Tomás L. Falzone¹, E. Cheng Chan², Malcolm J. Low², and Marcelo Rubinstein^{1, 3}

¹ Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, Universidad de Buenos Aires-Consejo Nacional de Investigaciones Científicas y Técnicas, 1428 Buenos Aires, Argentina, ² Vollum Institute, Oregon Health Sciences University, Portland, Oregon 97201, and ³ Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, 1428 Buenos Aires, Argentina

The pro-opiomelanocortin (POMC) gene is expressed in a subset of hypothalamic and hindbrain neurons and in pituitary melanotrophs and corticotrophs. POMC neurons release the potent opioid -endorphin and several active melanocortins that control homeostasis and feeding behavior. POMC gene expression in the CNS is believed to be controlled by distinct cis-acting regulatory sequences. To analyze the transcriptional regulation of POMC in neuronal and endocrine cells, we produced transgenic mice carrying POMC27*, a transgene containing the entire 6 kb of the POMC transcriptional unit together with 13 kb of 5' flanking regions and 8 kb of 3' flanking regions. POMC27* was tagged with a heterologous 30 bp oligonucleotide in the third exon. In situ hybridization studies showed an accurate cell-specific pattern of expression of POMC27* in the arcuate nucleus and the pituitary. Hypothalamic mRNA-positive neurons colocalized entirely with -endorphin immunoreactivity. No ectopic transgenic expression was detected in the brain. Deletional analyses demonstrated that neuron-specific expression of POMC transgenes required distal 5' sequences localized upstream of the pituitary-responsive proximal cis-acting elements that were identified previously. POMC27* exhibited a spatial and temporal pattern of expression throughout development that exactly paralleled endogenous POMC. RNase protection assays revealed that POMC27* expression mimicked that of POMC in different areas of the CNS and most peripheral organs with no detectable ectopic expression. Hormonal regulation of POMC27* and POMC was identical in the hypothalamus and pituitary. These results show that distal 5' sequences of the POMC gene located between 13 and 2 kb target expression into the CNS of transgenic mice in a precise neuron-specific, developmentally and hormonally regulated manner.

Key words: pro-opiomelanocortin; transgenic mice; gene expression; -endorphin; melanocortin; neuron-specific expression; arcuate nucleus; hypothalamus; pituitary

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Copyright © 1998 Society for Neuroscience  0270-6474/98/18176631-10$05.00/0

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