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Regulation of Start Site Usage in the Leader Exons of the Rat Insulin-Like Growth Factor-I Gene by Development, Fasting, and Diabetes

Section on Molecular and Cellular Physiology, Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health Bethesda, Maryland 20892

Address requests for reprints to: Dr. Martin L. Adamo, Diabetes Branch, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Building 10, Room 8S-243, Bethesda, Maryland 20892.

Abstract

Rat insulin-like growth factor-I (IGF-I) mRNAs with different 5'-untranslated region/prepeptide coding sequences result from transcription initiation in one of two leader exons. While not altering the mature IGF-I coding sequence, these different leaders potentially encode two distinct IGF-I prepeptides, one of 48 amino acids (exon 1) and one of 32 amino acids (exon 2). Within exon 1, transcription initiation is dispersed (i.e. occurs over a 350-basepair region), while within exon 2, it is highly localized. A fourth exon 1 start site, residing only approximately 30 basepairs from its 3' end, is suggested on the basis of RNase protection assays; its use would produce an mRNA encoding a third distinct IGF-I leader peptide of 22 amino acids. We have determined that during postnatal development, and as a result of insulinopenic diabetes and fasting, choice of transcription start sites within exon 1 in the liver is coordinately regulated, i.e. use of all start sites increased during development and decreased in the two catabolic states. Transcription initiation at the single major site within exon 2 was also reduced in diabetes and fasting. Insulin replacement therapy and refeeding restored the levels of all transcripts coordinately. During postnatal development, however, transcripts initiating within exon 2 exhibited a different developmental profile than did exon 1 transcripts, increasing especially at the onset of GHdependent linear growth. In liver, therefore, negative regulation of exon 1 and exon 2 transcription start site usage occurs in catabolic states, while in development, differential regulation of exon 1 and exon 2 transcription start sites occurs.

FOOTNOTES

This work was supported by grants from the Diabetes Research and Education Foundation (to D.L.R. and C.T.R.).

^* Recipient of a postdoctoral fellowship from the Juvenile Diabetes Foundation.

Received for publication July 18, 1991. Revision received September 9, 1991. Accepted for publication September 9, 1991.

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