J. Pathol. 186: 117–118 (1998)

EDITORIAL

THE ORIGIN OF GUT AND PANCREATICNEUROENDOCRINE (APUD) CELLS—THE LAST WORD?

. 1, . 1 . . 2*1Department of Anatomical Sciences, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road,

Parktown 2193, Johannesburg, South Africa2Department of Anatomy and Cell Biology, University of Cape Town Medical School, Observatory,

7925, Cape Town, South Africa

SUMMARY

The evidence that gut and pancreatic endocrine cells are not derivatives of the neural crest is overwhelming: yet this conclusion is stillnot universally accepted. In this editorial attention is drawn to the body of experimental evidence which points conclusively to gut andpancreatic endocrine cells arising from endoderm, not the neural crest, the neurectoderm or neuroendocrine programmed epiblast.? 1998 John Wiley & Sons, Ltd.

KEY WORDS—APUD cells; Apudomas; endocrine glands; gastrointestinal hormones; neural crest; neuroendocrine tumours

*Correspondence to: B. B. Rawdon, Department of Anatomy andCell Biology, University of Cape Town Medical School, Observatory,7925, Cape Town, South Africa.

In an editorial in 1983,1 we drew attention to theoverwhelming evidence that gut and pancreatic endo-crine cells are not derivatives of the neural crest.Although this conclusion has been accepted by many,and for pancreatic endocrine cells by as prominent aworker as Slack,2 a well-known textbook3 still categori-cally proclaims the source to be the neural crest. Sincerecent reviews4,5 do not provide complete accounts ofthe evidence presented in the literature, we are promptedto return to the issue.

It is essential to appreciate the nature of evidencerequired for a valid conclusion to be drawn about theembryonic origin of any group of cells. Although sharedcharacteristics of APUD (neuroendocrine) cells, inparticular, neurones and gut and pancreatic endocrinecells, legitimately spawned and were used to support thehypothesis of a common origin, this hypothesis had tobe subjected to experimental testing. Likewise, theobservation of an inherent feature, or even tritiatedthymidine uptake, in both presumptive stem cells anddifferentiated cells, although interpreted as a process,6–8

is only consistent with derivation of the latter from theformer and does not constitute proof. In the presentcontext, experimental tests included elimination of thepostulated source (neural crest or neurectoderm)9–11 andmarking such a source with a durable marker such astritiated thymidine12,13 or, better, the quail nucleolarmarker, used extensively by Le Douarin and co-workersand by us in experiments referred to below. Further-more, to refine the conclusion regarding the origin ofthe gut and pancreatic endocrine cells, the presence of

CCC 0022–3417/98/100117–02$17.50? 1998 John Wiley & Sons, Ltd.

the individual cell types concerned had to be verifiedin the experimental material.

A brief chronological list of the experimental studiesfollows. Except for subsequent publications,14,15 this isfully and critically reviewed elsewhere.16 With regard topancreatic endocrine cells, Pictet et al.11 showed thatinsulin cells are not ectodermal in origin; Dieterlen-Lièvre and Beaupain17 that insulin and glucagon cellsare unlikely to be neural crest derivatives; Andrew13 andthen Fontaine et al.18 that pancreatic islets are notderived from the trunk neurectoderm; Andrew andKramer19 that at least insulin and glucagon cells are notof rhombencephalic neurectodermal origin; Fontaine-Pèrus et al.20 that this is also true for somatostatin cells;and Kramer and Andrew14 that none of insulin, gluca-gon, and somatostatin cells originate in neurectoderm.The endodermal origin of these cell types was supportedin other work by Andrew et al.1 Hence, it is obvious thatthe three major pancreatic endocrine cell types are notderived from the neural crest.

With regard to gut endocrine cells, Andrew9,10

showed enterochromaffin (EC) cells not to be neurecto-dermal derivatives; Le Douarin and Teillet21 found noneural crest cells in the endoderm; and Fontaine and LeDouarin22 saw no ectoblast cells in the endoderm, inwhich they identified EC cells. Lamers et al.12 detectedno neural crest cells in gut epithelium; and Andrewet al.15 demonstrated gut endocrine cells to be of endo-dermal, not ectodermal or mesodermal origin. The latterfinding embraced EC cells and practically all thepeptide-secreting cell types. Hence, gut endocrine cellstoo are not derived from the neural crest, but fromendoderm.

Pearse’s contention23 that all APUD cells originatein the neural crest triggered the above experimental

Received 22 April 1998Accepted 20 May 1998

118 EDITORIAL

investigation of the embryonic origin of gut and pancre-atic endocrine cells. However, as the results of thesestudies came through, he proposed first neurectoderm24

and subsequently ‘neuroendocrine-programmed ecto-blast’25 or ‘neuroendocrine-programmed epiblast’26 asthe source. The reviewers mentioned above4,5 favourneuroendocrine-programmed epiblast as the source butthe data should be more critically reviewed. AlthoughPearse27 more recently suggests that gut and pancreaticendocrine cells share a stem cell with other epithelialcell types in the gut, even now he does not exclude thepossibility that they are neuroectodermal derivatives.

As stated by Le Douarin,28 neuroendocrine-programmed ectoblast, but not epiblast, has beenprecluded by her experimentation.22 It is difficult to see away of testing the latter directly. A theoretical consid-eration of the hypothesis is provided by Andrew,29 butan answer for gut endocrine cells has come from adifferent source. Clonal work has demonstrated differ-entiation of gut endocrine cells of types unspecified,except for gastrin cells,30 together with other epithelialcell types, from the same stem cell present in neo-plastic31,32 or normal30,33 gut epithelium. These findingsmake untenable the postulate that neuroendocrine-programmed epiblast is the common source of gutendocrine and other APUD/neuroendocrine cells. Com-parable stem cell studies are not at present applicable topancreatic endocrine cells2 to affirm their origin fromendoderm. However, a different explanation for thesharing of certain characteristics with neurones devolvesrather upon acquisition of these characteristics later on,during differentiation. The detection of the expression ofseveral of the same genes in the pancreas and parts ofthe nervous system during embryonic development,34–37

and especially the requirement for this expression fordevelopment of islet cells and motor neurons,35 points tothe same transcriptional control mechanisms operatingduring differentiation of endocrine cells and neurones.Thus, neurones and gut and pancreatic endocrine cells,rather than sharing a common embryological origin,are related by their common biochemical features.Acquisition of these features, seen by many as ‘neuro-endocrine programming’, occurs during differentiation,not in the epiblast.

REFERENCES1. Andrew A, Kramer B, Rawdon BB. Gut and pancreatic amine precursor

uptake and decarboxylation cells are not neural crest derivatives. Gastro-enterology 1983; 84: 429–431.

2. Slack JMW. Developmental biology of the pancreas. Development 1995;121: 1569–1580.

3. Ganong WF. Review of Medical Physiology, 16th edn. Connecticut/California: Appleton and Lange. 1993; 441.

4. Delcore R, Friesen SR. Embryologic concepts in the APUD system. SeminSurg Oncol 1993; 9: 349–361.

5. Langley K. The neuroendocrine concept today. Ann NY Acad Sci 1994; 773:1–17.

6. Pearse AGE, Polak JM. Neural crest origin of the endocrine polypeptide(APUD) cells of the gastrointestinal tract and pancreas. Gut 1971; 12:783–788.

7. Cheng H, Leblond CP. Origin, differentiation and reneweal of the four mainepithelial cell types in the mouse small intestine. V. Unitarian theory of theorigin of the four epithelial cell types. Am J Anat 1974; 141: 537–562.

8. Teitelman G, Joh TH, Reis DJ. Transformation of catecholaminergicprecursors into glucagon (A) cells in mouse embryonic pancreas. Proc NatlAcad Sci USA 1981; 78: 5225–5229.

? 1998 John Wiley & Sons, Ltd.

9. Andrew A. A study of the developmental relationship between enterochro-maffin cells and the neural crest. J Embryol Exp Morphol 1963; 11: 307–324.

10. Andrew A. Further evidence that enterochromaffin cells are not derivedfrom the neural crest. J Embryol Exp Morphol 1974; 31: 589–598.

11. Pictet RL, Rall LB, Phelps P, Rutter WJ. The neural crest and the origin ofthe insulin-producing and other gastrointestinal hormone-producing cells.Science 1976; 191: 191–193.

12. Lamers CHJ, Rombout JWHM, Timmermans LPM. An experimentalstudy on neural crest migration in Barbus conchonius (Cyprinidae, Teleostei)with special reference to the origin of the enteroendocrine cells. J EmbryolExp Morphol 1981; 62: 309–323.

13. Andrew A. An experimental investigation into the possible neural crestorigin of pancreatic APUD (islet) cells. J Embryol Exp Morphol 1976; 35:577–593.

14. Kramer B, Andrew A. Further investigation into the source of pancreaticendocrine cell types. Gen Comp Endocrinol 1981; 44: 279–287.

15. Andrew A, Kramer B, Rawdon BB. The embryonic origin of endocrine cellsof the gastrointestinal tract. Gen Comp Endocrinol 1982; 47: 249–265.

16. Andrew A. APUD cells and paraneurons: embryonic origin. In: Federoff S,Hertz L, eds. Advances in Cellular Neurobiology, Volume 2. New York:Academic Press, 1981; 3–32.

17. Dieterlen-Lièvre F, Beaupain D. Immunocytological study of endocrinepancreas ontogeny in the chick embryo: normal development and pancreaticpotentialities in the early splanchnopleure. In: Grillo TAI, Liebson L, EppleA, eds. The Evolution of Pancreatic Islets. Oxford: Pergamon Press, 1976;37–50.

18. Fontaine J, Le Lièvre C, Le Douarin NM. What is the developmental fateof the neural crest cells which migrate into the pancreas in the avianembryo? Gen Comp Endocrinol 1977; 33: 394–404.

19. Andrew A, Kramer B. An experimental investigation into the possibleorigin of pancreatic islet cells from rhombencephalic neurectoderm.J Embryol Exp Morphol 1979; 52: 23–33.

20. Fontaine-Pèrus J, Le Lièvre C, Dubois MP. Do neural crest cells in thepancreas differentiate into somatostatin-containing cells? Cell Tissue Res1980; 213: 293–299.

21. Le Douarin N, Teillet M-A. The migration of neural crest cells to the wallof the digestive tract in avian embryo. J Embryol Exp Morphol 1973; 30:31–48.

22. Fontaine J, Le Douarin NM. Analysis of endoderm formation in the avianblastoderm by the use of quail-chick chimaeras. The problem of theneuroectodermal origin of the cells of the APUD series. J Embryol ExpMorphol 1977; 41: 209–227.

23. Pearse AGE, Welsch U. Ultrastructural characteristics of the thyroid C cellsin the summer, autumn and winter states of the hedgehog (Erinaceuseuropaeus L.) with some reference to other mammalian species. Z ZellforschMikrosk Anat 1968; 92: 596–609.

24. Pearse AGE. The endocrine division of the nervous system: a logicalextension of the APUD concept. Folia Anat Iugoslavica 1975; 4: 5–20.

25. Pearse AGE. The diffuse neuroendocrine system and the APUD concept:related endocrine peptides in brain, intestine, placenta and anurancutaneous glands. Med Biol 1977; 55: 115–125.

26. Pearse AGE, Takor Takor T. Embryology of the diffuse neuroendocrinesystem and its relationship to the common peptides. Fed Proc 1979; 38:2288–2294.

27. Pearse AGE. Genesis of the neuroendocrine system. In: Friesen SR,Thompson NW, eds. Surgical Endocrinology. Philadelphia: Lippincott,1990; 15–23.

28. Le Douarin N. On the origin of pancreatic endocrine cells. Cell 1988; 53:169–171.

29. Andrew A. Developmental relationships of neuroendocrine cells. BiomedRes 1985; 6: 191–196.

30. Thompson EM, Fleming KA, Evans DJ, Fundele R, Surani MA, WrightNA. Gastric endocrine cells share a clonal origin with other gut cell lineages.Development 1990; 110: 477–481.

31. Cox WF, Pierce GB. Endodermal origin of the endocrine cells of anadenocarcinoma of the colon of the rat. Cancer 1982; 50: 1530–1538.

32. Kirkland SC. Clonal origin of columnar, mucous and endocrine cell lineagesin human colorectal epithelium. Cancer 1988; 61: 1359–1363.

33. Novelli MR, Williamson JA, Tomlinson IPM, Elia G, Hodgson SV, TalbotIC, Bodmer WF, Wright NA. Polyclonal origin of colonic adenomas in anXO/XY patient with FAP. Science 1996; 272: 1187–1190.

34. Alpert S, Hanahan D, Teitelman G. Hybrid insulin genes reveal a develop-mental lineage for pancreatic endocrine cells and imply a relationship withneurons. Cell 1988; 53: 295–308.

35. Ahlgren U, Pfaff SL, Jessell TM, Edlund T, Edlund H. Independentrequirements for ISL1 in formation of pancreatic mesenchyme and isletcells. Nature 1997; 385: 257–260.

36. Sosa-Pineda B, Chowdhury K, Torres M, Oliver G, Gruss P. The Pax4 geneis essential for differentiation of insulin-producing â cells in the mammalianpancreas. Nature 1997; 386: 399–402.

37. St-Onge L, Sosa-Pineda B, Chowdhury K, Mansouri A, Gruss P. Pax6is required for differentiation of glucagon-producing á-cells in mousepancreas. Nature 1997; 387: 406–409.

J Pathol. 186: 117–118 (1998)