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Corticotropin-Releasing Factor (CRF)-Like Immunoreactivity in the Vertebrate Endocrine Pancreas (Immunocytochemistry/Hormones/Islets of Langerhans/Evolution) P

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Corticotropin-Releasing Factor (CRF)-Like Immunoreactivity in the Vertebrate Endocrine Pancreas (Immunocytochemistry/Hormones/Islets of Langerhans/Evolution) P Proc. NatL Acad. Sci. USA Vol. 80, pp. 1721-1725, March 1983 Medical Sciences Corticotropin-releasing factor (CRF)-like immunoreactivity in the vertebrate endocrine pancreas (immunocytochemistry/hormones/islets of Langerhans/evolution) P. PETRUSZ*, I. MERCHENTHALER*, J. L. MADERDRUTt, S. VIGHt, AND A. V. SCHALLY* *Department of Anatomy, University of North Carolina, Chapel Hill, North Carolina 27514; tNeuroembryology Laboratory, Dorothea Dix Hospital, Raleigh, North Carolina 27611; and *Endocrine and Polypeptide Laboratories, Veterans Administration Medical Center and Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana 70146 Contributed by Andrew V. Schally, December 23, 1982 ABSTRACT The light microscopic immunocytochemical lo- MATERIALS AND METHODS calization of corticotropin-releasing factor (CRF) is described in the endocrine pancreas of several species representing the major Sources of Tissues. Five adult male Sprague-Dawley rats classes of vertebrates: fishes (channel catfish, Ictalurus puncta- were obtained from ARS/Sprague-Dawley (Madison, WI). One tus), amphibians (African clawed toad, Xenopu8 laevis), reptiles Sprague-Dawley rat and one White Leghorn chicken (Gallus (chameleon, Anolis carolinensis), birds (chicken, Gallus domesti- domesticus) were sacrificed at approximately 1 day of age. Three cus), and several mammals (rat, mouse, cat, rhesus monkey, and adult female mice (C57BL/6J) were obtained from Blue Spruce man). The CRF-containing cells are scattered over the entire islet Farms (Altamont, NY). One African clawed toad (Xenopus lae- tissue in primates and cat, whereas in rat and mouse they are lo- vis) and pancreatic tissue from two channel catfish (Ictalurus cated at the periphery of the islets. In the chicken and catfish, the punctatus) were gifts from L. J. Haverkamp (Neurobiology Pro- CRF-containing cells are found in a central location within islets gram, University of North Carolina) and J. E. Brinn (Depart- and form larger clusters or cords. Single cells with CRF-like im- ment of Anatomy, East Carolina University), respectively. Three munoreactivity are interspersed between acinar cells of the exo- lizards (Anolis carolinensis) were purchased from Carolina Bi- crine pancreas in all species studied. The CRF cells show a sub- ological Supply (Burlington, NC). Pancreatic tissue from two stantial topographical overlap with glucagon cells, but their precise adult cats and two adult rhesus monkeys (Macaca mulatta) also identity and function remain to be determined. was studied. Human pancreas (courtesy of E. K. MacRae and F. D. Dalldorf) was from a 1-year-old infant who died in an ac- Corticotropin-releasing factor (CRF), a 41-amino acid peptide, cident. has been isolated and characterized from extracts of ovine hy- Preparation of Tissues. pothalamus as a potent stimulator of the secretion of cortico- Rat, mouse, cat, monkey, chicken, tropin (ACTH) and 3-endorphin (1-3). Immunocytochemical toad, and lizard tissues were fixed by perfusion with 4% para- studies have established that most of the CRF in the hypo- formaldehyde as described (22). The pancreata from both the thalamus is located both in neurons of the paraventricular nu- human and the catfish were fixed by immersion, the former in cleus and in terminals around portal capillaries of the median 10% formalin and the latter in Bouin's solution. Fixation was eminence (4-7). CRF-like immunoreactivity has been identi- followed by washing, dehydration, and embedding in paraffin. fied in hypophysial portal blood (8). The neural pathways through Serial sections were cut at 5 or 8 1Am. which CRF reaches the median eminence also have been de- Antisera. All primary antisera (except the antiinsulin serum) scribed (9). Like other neuropeptides, CRF is widely distrib- were prepared in rabbits. The antiserum to CRF (SV-22) was uted in extrahypothalamic areas of the brain, determined by made by coupling synthetic ovine CRF (gift from D. H. Coy, both radioimmunoassay (10) and immunocytochemistry (11-13). Department of Medicine, Tulane University) to bovine serum In addition to stimulating the release of ACTH and /8-endor- albumin with glutaraldehyde (7). The glucagon antiserum (R-32) phin, CRF has a broad range of pharmacological effects, which against highly purified porcine glucagon was a gift from K. P. include changes in behavior, heart rate, blood pressure, and in Lund (Department of Physiology, University of North Caro- blood concentrations of epinephrine, norepinephrine, gluca- lina) and D. J. Sanders (Department of Physiology, Medical gon, and glucose (14-18). Thus, CRF appears to be an important School, Newcastle upon Tyne, England). The antiserum rec- regulatory peptide mediating stress-related physiological re- ognizes the midportion of the glucagon molecule and binds both sponses and predictably possessing other, hitherto unsus- pancreatic glucagon and its precursors. The antiserum (6-F) to pected, hormone- or neurotransmitter-like activities. On the somatostatin (somatotropin release-inhibiting factor, SR-IF) was basis of current hypotheses concerning the common evolution- made by using synthetic SR-IF-14 coupled to bovine thyro- ary origin of hormones and neurotransmitters (19-21), CRF may globulin with glutaraldehyde and was a gift from E. R. Perl (De- be expected to occur at peripheral sites, such as autonomic and partment of Physiology, University of North Carolina). The in- sensory ganglia or nerve fibers and terminals, or in endocrine sulin antiserum (no. 7) was raised in a guineapig against purified cells scattered in a variety of organs. porcine insulin and was a gift from L. E. Underwood (Depart- This report describes the immunocytochemical localization ment of Pediatrics, University of North Carolina). The anti- of CRF-like immunoreactivity in the endocrine pancreas in rep- serum to bovine pancreatic polypeptide (PP) was purchased from resentative species of the major classes of vertebrates, includ- Accurate Chemical (Westbury, NY). Optimal dilutions for all ing man. antisera ranged between 1:2,000 and 1:10,000. The publication costs of this article were defrayed in part by page charge Abbreviations: ACTH, corticotropin; CRF, corticotropin-releasing fac- payment. This article must therefore be hereby marked "advertise- tor; PP, pancreatic polypeptide; SR-IF, somatotropin release-inhibiting ment" in accordance with 18 U. S. C. §1734 solely to indicate this fact. factor or somatostatin. 1721 Downloaded by guest on September 25, 2021 1722 Medical Sciences: Petrusz et al. Proc. Natl. Acad. Sci. USA 80 (1983) Immunocytochemistry. Slides were deparaffinized and stained Del Rey, CA), 'y-endorphin (Peninsula Laboratories, San Car- by using the peroxidase-antiperoxidase complex (Stemberger- los, CA), bovine PP (gift from R. E. Chance, Lilly Research Meyer Immunocytochemicals, Jarrettsville, MD) according to Laboratories, Indianapolis, IN), and synthetic human gastrin I, the "double PAP" method (23). The distribution of CRF was motilin, secretin, gastric inhibitory peptide, and vasoactive in- compared to that of other pancreatic hormones by localizing two testinal polypeptide (gifts from D. H. Coy, Tulane University). antigens in the same section with contrasting chromogens (24). The anti-CRF serum also has been characterized by immuno- Controls. Method specificity (25) was tested by a series of diffusion and radioimmunoassay (7) and by immunocytochem- increasing dilutions of the primary antiserum, resulting in a istry on brain tissue (9, 11). gradual decrease and eventual disappearance of the immuno- Sections stained for the simultaneous localization of two an- staining. Antiserum specificity was tested by absorption of the tigens, and adjacent sections stained alternatively for CRF and anti-CRF serum with synthetic CRF, bovine insulin (Sigma), either insulin, glucagon, SR-IF, or PP, provided additional con- glucagon (Sigma), synthetic SR-IF-14 (Beckman Bioproducts, trols of specificity. These techniques also were used in attempts Palo Alto, CA), pentagastrin (Bachem Fine Chemicals, Marina to determine whether CRF-like immunoreactivity occurred in E Al ~ It.- ., -vHe C~ '* a ' :-;_ ;- '4 t -KI, .I I 0 A sdki A, 'VF i f At KW. i: EP .F -i .v I (I O...~O *:: i.*, _ V -.1~~~~~~~~~~~~~~~. J AA An, '-I t__ Hi. '44 ?I' s- v .ii, e.j '.- & ^ - -r Zt l. 19A"L, .s '-' i mS. r l2- D .* ' _. rvf a ¶F 45 -e 7 I "be fb -0~~~~~~~~~~~~~~~~~~DJo ::~~~~~~ -,frit#s*Ej -i Ut.... w .~~~~~ A.~~ rrt 4* 'sOt*' I E 4m. h t) FIG. 1. CRF-like immunoreactivity in pancreatic tissue. (A) Islet of Langerhans from.the mouse pancreas. Note peripheral localization of CRF cells. (x250.) (B) CRF cell in the exocrine pancreas of the toad (X. laevis). The cell is wedged between exocrine cells at the periphery of an acinus. (x 1,000.) (C) Cat pancreas. A cluster of CRF cells is attached to a nerve ganglion (*) located in the interlobular connective tissue. EP, exocrine pancreas. (x250.) (D) Islet of Langerhans from the cat pancreas. CRF cells are present both at the periphery and in the central regions of the islet. (x400.) (E) Islet of Langerhans from the pancreas of a 1-year-old human. The CRF cells are scattered in all regions of the islet. (x250.) (F) Islet of Langerhans from the pancreas of a rhesus monkey. The CRF cells are distributed evenly over the entire islet. (x 250.) Downloaded by guest on September 25, 2021 Medical Sciences: Petrusz et al. Proc. Natl. Acad. Sci. USA 80 (1983) 1723 the same cells together with any of the known pancreatic hor- confirming the observations of Hokfelt et aL (26). In the human, mones. The results were analyzed with a Zeiss Universal mi- the monkey, and the cat, the cells with CRF-like immunoreac- croscope equipped with a drawing attachment (camera lucida). tivity were scattered throughout the islets, with only a slight tendency for greater numbers to occur at the periphery (Fig. 1 RESULTS D-F). However, larger areas (sometimes as much as one-third) Immunoreactive CRF was detected in pancreatic cells in all of of certain islets were completely free of CRF cells. A small pro- the species studied (Figs. 1, 2, and 3). There was substantial portion of the islets did not appear to contain any CRF at all.
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