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The Secretin Gene: Evolutionary History, Alternative Splicing, and Developmental Regulation (Intestine/Preprohormone/Polymerase Chain Reaction) ALAN S

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The Secretin Gene: Evolutionary History, Alternative Splicing, and Developmental Regulation (Intestine/Preprohormone/Polymerase Chain Reaction) ALAN S Proc. Nati. Acad. Sci. USA Vol. 88, pp. 5335-5339, June 1991 Biochemistry The secretin gene: Evolutionary history, alternative splicing, and developmental regulation (intestine/preprohormone/polymerase chain reaction) ALAN S. KOPIN*t, MICHAEL B. WHEELER*, JUNKO NISHITANI*, EDWARD W. MCBRIDE*, TA-MIN CHANGt, WILLIAM Y. CHEYt, AND ANDREW B. LEITER* *Division of Gastroenterology, New England Medical Center, Tufts University School of Medicine, Boston, MA 02111; and tIsaac Gordon Center for Digestive Diseases and Nutrition, The Genesee Hospital, University of Rochester School of Medicine and Dentistry, Rochester, NY 14609 Communicated by Viktor Mutt, March 26, 1991 (receivedfor review January 8, 1991) ABSTRACT The gene encoding the hormone secretin has gene differs in structure from other genes of the glucagon- been isolated and structurally characterized. The transcrip- secretin family. Similarities within the gene family appear to tional unit is divided into four exons spanning 813 nucleotides. be limited to the exons that encode the biologically active Comparison ofthe rat secretin gene to the other members ofthe peptides. glucagon-secretin gene family reveals that similarities are We have reported (1) the tissue distribution of secretin restricted to the exons encoding the biologically active peptides. mRNA within the rat gastrointestinal tract. Unexpectedly, Analysis of RNA from porcine intestine indicates that at least the highest levels of secretin mRNA were found in the ileum, two transcripts are generated from the porcine secretin gene as distant from the regions of the intestine that are exposed to a result of differential splicing. The longer and more abundant the highest concentrations of gastric acid and fat, the major transcript appears to be identical to a previously isolated stimuli for secretin release (4-6). To further investigate the cDNA, which encodes a precursor that includes a 72-amino acid relationship between secretin gene expression and the pres- C-terminal extension peptide. The shorter transcript does not ence of its enteral secretagogues, we have examined the contain the third exon and, as a result, encodes only 44 residues ontogeny of this hormone in developing rats. The develop- beyond the C terminus of secretin. The amino acid sequence mental studies reported here demonstrate that intestinal deduced from the shorter transcript is identical to a precursor secretin mRNA levels are highest before birth, antedating the form of secretin recently isolated from porcine duodenum onset of gastric acid production and feeding. These obser- [Gafvelin, G., Jornvall, H. & Mutt, V. (1990) Proc. Natl. Acad. vations suggest that the secretin gene is developmentally Sci. USA 87, 67814785]. Developmental studies reveal that regulated by factors other than its established enteral secre- both secretin mRNA and peptide levels in the intestine are tagogues. highest just before birth, prior to the onset of gastric acid secretion and feeding. This observation implies that secretin biosynthesis in developing animals is controlled independently MATERIALS AND METHODS of the principal factors known to regulate secretin release in Isolation of Recombinant Bacteriophage Containing the Rat adult animals. Secretin Gene. A library constructed from a partial Hae III digest ofrat genomic DNA and propagated in A Charon 4A (7) We have described (1) the isolation of cDNAs encoding was screened with a 424-base rat secretin cDNA probe porcine and rat secretin precursors. The deduced structures labeled by priming with random hexamers (8). Of 500,000 of the rat and porcine secretin precursors are similar, con- plaques examined, 4 positive recombinants were identified. sisting ofa signal peptide, an N-terminal peptide, secretin, an A 2.6-kilobase EcoRI restriction fragment was isolated from amidation-cleavage sequence, and a 72-amino acid C-termi- plaque-purified phage DNA, subcloned into the plasmid nal peptide. A precursor form of porcine secretin extending pUC19, and sequenced by the chain-termination method (9) only 44 amino acids beyond secretin has recently been using modified T7 DNA polymerase (United States Biochem- purified from intestinal extracts and sequenced (2). Within ical). Computer analysis of nucleotide and deduced peptide the C-terminal peptide of the shorter precursor, a single sequences utilized the University of Wisconsin Genetics arginine residue replaced 32 amino acids predicted from the Computer Group Software version 6.3 (10). cDNA. The remaining 40 amino acids at the C terminus ofthe Determination of the Transcriptional Initiation Site. The short precursor were identical to the sequence derived from transcriptional initiation site was mapped using a 32P-end- the cDNA. We now report the identification of differentially labeled (1 x 107 cpm/pmol) 24-base oligonucleotide probe, spliced secretin transcripts in porcine intestine that account 5'-GTGCAGGAAGCACGAAAGAACTTG-3'. The primer for both precursor forms. was annealed to poly(A)+ RNA (5.8 ,ug) isolated from rat Secretin is structurally related to several other regulatory small intestinal mucosa for 2 hr at 60°C in 250 mM KCl/10 peptides including glucagon, vasoactive intestinal peptide mM Tris Cl, pH 7.5/1 mM EDTA. Transcripts were extended (VIP), gastric inhibitory polypeptide (GIP), growth hormone- for 1 hr at 37°C using Moloney murine leukemia virus reverse releasing hormone (GHRH), and pituitary adenylate cyclase- transcriptase. The size of the extended product was deter- activating protein, based on the occurrence of common mined by electrophoresis on a denaturing 8% polyacrylamide N-terminal amino acids (3). To further understand the evo- gel. lutionary relationship of secretin with other members of its Northern Blot Hybridization Assays. RNA from intestinal peptide family, we have isolated and structurally character- tissue of fetal and postnatal rats (Taconic Farms) was pre- ized the rat secretin gene.§ We found that the rat secretin Abbreviations: VIP, vasoactive intestinal peptide; GIP, gastric in- hibitory polypeptide; GHRH, growth hormone-releasing hormone. The publication costs of this article were defrayed in part by page charge tTo whom reprint requests should be addressed. payment. This article must therefore be hereby marked "advertisement" §The sequence reported in this paper has been deposited in the in accordance with 18 U.S.C. §1734 solely to indicate this fact. GenBank data base (accession no. M64033). 5335 Downloaded by guest on September 28, 2021 5336 Biochemistry: Kopin et al. Proc. Natl. Acad. Sci. USA 88 (1991) pared by extraction in acid phenol (11). For Northern blot encoding porcine secretin and the end of its C-terminal analyses, equal amounts of RNA were separated on 1.3% peptide. After heating at 980C for 5 min, the reaction mixture agarose/0.66 M formaldehyde gels and transferred to Nytran was cooled to 720C, and 2.5 units of Thermus aquaticus (Taq) membranes by capillary blotting. Blots were hybridized at DNA polymerase (Perkin-Elmer/Cetus) was added. DNA high stringency with the same secretin cDNA probe used to was amplified through 30 cycles of denaturation at 940C for screen the genomic library. To assure that equal amounts of 60 sec followed by a one-step annealing/extension at 680C for RNA were loaded into each lane, the RNA was quantitated 60 sec. A 133-bp Apa I-Sst I fragment ofa 201-bp product was by the absorbance at 260 nM, and the blots were reprobed for subcloned and sequenced. 13-actin. Selected blots were rehybridized with a rat chole- Determination of Secretin-Like Immunoreactivity in Tis- cystokinin cDNA probe at high stringency (12). The relative sues. Intestinal tissue was rapidly removed from rats of abundance of secretin mRNA on the autoradiographs was selected ages, frozen in liquid nitrogen, and stored at -70°C. determined by scanning densitometry. Radioimmunoassay for secretin-like immunoreactivity in in- Ribonuclease Protection Assays. Porcine or rat intestinal testinal extracts was performed as described (14). RNA samples were hybridized overnight at 45°C (13) with 2-10 fmol of antisense RNA probes (105 cpm/fmol). The probes consisted of a sequence complementary to a 366- RESULTS nucleotide Sal I-Nco I restriction fragment ofthe rat secretin Isolation of the Rat Secretin Gene. Screening -500,000 cDNA plus 42 nucleotides of pIBI31 vector and a 229-base- plaques in a rat genomic library with a rat secretin cDNA pair (bp) Nco I-BamHI restriction fragment of the porcine probe identified 4 identical clones. Southern blot analysis of secretin cDNA plus 37 bp of pGEM-5 vector. The hybrids the phage DNA revealed that the rat secretin cDNA probe were digested with RNase A (30 ,g/ml) and RNase T1 (2 hybridized to a single 2.6-kilobase EcoRI restriction frag- ,ug/ml) at 25°C for 30 min and the size of the protected ment. The same fragment hybridized to oligonucleotide fragments was determined by electrophoresis on denaturing probes specific for the 5' and 3' untranslated regions of the 5% polyacrylamide gels. mRNA, suggesting that the entire transcription unit was cDNA Amplification. Oligo(dT)-primed first-strand cDNA isolated. was reverse-transcribed from poly(A)+ porcine duodenal Nucleotide Sequence Analysis of the Cloned Rat Secretin mucosal RNA for use as template in the polymerase chain Gene. The rat secretin gene spans 813 nucleotides from the reaction as described (1). Amplification of 100 ng oftemplate transcriptional start site to the polyadenylylation addition was primed with two oligonucleotides, 5'-GACACTCG-
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