Talk:Paper - The timing and sequence of events in the development of the human endocrine system during the embryonic period proper
Anat Embryol (1983) 166:439-451 Anatomy and Embryology
The Timing and Sequence of Events in the Development of the Human Endocrine System During the Embryonic Period Proper*
Ronan O’Rahilly
Carnegie Laboratories of Embryology, California Primate Research Center, and Departments of Human Anatomy and Neurology, University of California, Davis, California 95616, U.S.A.
Summary. A documented scheme of the early development of the human endocrine system is presented. It is based on (1) reports of workers who personally studied staged embryos, and (2) personal observations and confirmations. The necessity of using staged embryos in order to determine the precise sequence of developmental events is stressed.
Key words: Human embryo — Endocrine system — Hypophysis cerebri — Thyroid gland — Developmental stages
Introduction
Observations on the development of individual endocrine organs may be found in many widely-scattered articles on embryology, and a number of papers specifically on those organs have been published. However, apart from the valuable but limited information provided by Jirasek (1980), no comprehensive account of the early development of the human endocrine system seems to be available, certainly not with reference to staged embryos, such as have been published in regard to other systems of the body (O’Rahilly 1979). The importance of embryonic staging has been stressed repeatedly and it has been pointed out that the term ,,stage“‘ should be employed only in its technical, embryological sense. Such expressions as “‘at the 3 mm stage”’ should be replaced by “‘at 3 mm.”
Material and Methods
The scheme presented here is based on first-hand reports of workers who personally studied staged human embryos, supplemented by personal observations and confirmations of the present writer. Only staged embryos have been considered, that is, those specifically assigned
Offprint requests to: Professor R. O’Rahilly, Carnegie Laboratories of Embryology (C.P.R.C.), University of California, Davis, California 95616 U.S.A.
- Supported by research grant No. HD-16702, Institute of Child Health and Human Development, National Institutes of Health (U.S.A.)
440 R. O’Rahilly
to one of the recognized Carnegie stages. Certain early embryos, the stages of which were not specified, have here been assigned to stages on the basis of their somitic count. Moreover, Carnegie embryos that were described prior to the establishment of the staging system have since been staged. For example, regarding Weller’s (1933) important study, the following list indicates the stages described and illustrated: stage 9 (No. 1878), 10 (391; 3709), 13 (76; 800; 836), 14 (2841; 4672), 15 (4602), 16 (397; 1836), 17 (623; 695), 18 (74; 175; 492; 4430), 20 (966), and 23 (4570).
Results
In this article the following major organs will be considered at various developmental stages; hypophysis cerebri (pituitary gland); epiphysis cerebri (pineal body); pharyngeal pouches including thymus and parathyroid glands; thyroid gland; suprarenal cortex and medulla; and pancreas. The testis, ovary, and placenta will not be considered here, nor will less discrete endocrine components, such as those in the alimentary canal and kidney.
Sequence of Events Stage 9 (ca. 1.5—2.5 mm; 1-3 pairs of somites; ca 20 days):
Pharyngeal Pouches. The foregut is present and its recess includes the embryonic pharynx. The first pharyngeal pouches are identifiable (Ingalls 1920).
Thyroid. The thyroid primordium is probably not yet evident (Jimenez Collado and Ruano Gil 1963). Several workers (e.g., Weller 1933) had previously identified a thyroid proliferation at stage 9.
Stage 10 (ca. 2-3.5 mm; 4-12 pairs of somites; ca. 22 days):
Hypophysis. The site of the craniopharyngeal invagination is detectable 1mmediately rostral to the oropharyngeal membrane (Bartelmez and Dekaban 1962). The overlying neuro-ectoderm is the infundibular area, and the hypophysis arises at a single locus, not from two distinct evaginations that approach each other and fuse (O’Rahilly 1973).
Pharyngeal Pouches. The second pharyngeal pouches are identifiable (Bartelmez and Evans 1926) and the third pouches are perhaps indicated by 10 pairs of somites (Corner 1929).
Thyroid. Payne (1925) identified the thyroid primordium as “a thickening in the floor of the pharynx” at 7 pairs of somites.
The thyroid area has been identified at 8s. by Bartelmez and Evans (1926) but Politzer (1930) believed that the median swelling of the foregut (medianer Wulst des Vorderdarmes) 1s not the thyroid Anlage.
The ‘“‘primordium of thyroid gland” or “‘thyroid pouch”’ is visible “ between the diverging aortae”’ at 10s. (Corner 1929).
Stage 11 (ca. 2.5-4.5 mm; 13-20 pairs of somites; ca. 24 days):
Pharyngeal Pouches. The fourth pharyngeal pouches may appear (Davis 1923). Development of Human Endocrine System 444
Thyroid. The thyroid primordium at 13-14 s. shows a high level of alkaline phosphatase (Mori 1959).
The thyroid primordium at 14s. comprises an outgrowth (pouch) and a bud (Heuser 1930).
The thyroid at 17s. is a spherical nodule, the epithelial cells of which are higher and pseudostratified (Wen 1928). It is situated between the first and second pharyngeal pouches, and immediately caudal to the bifurcation of the aorta (ibid.).
The pit-like depression that has so often been described as the thyroid is formed by a moulding of the pharyngeal floor to conform with the irregularities of the dorsal surface of the heart at 17s. (Davis 1923; Atwell 1930).
Only a part of the median swelling at 18 s. represents the thyroid Anlage (Politzer 1928).
What Davis (1923) interpreted as fourth pharyngeal pouches at 20s., Weller (1933) termed “lateral thyroid” primordia.
The thyroid is the thickened nodule “considerably farther” rostral to the median pit (Davis 1923). Its “intermediate part is distinctly bilobed” at 20 s. (ibid.).
Stage 12 (ca. 3-5 mm; 21-29 pairs of somites; ca. 26 days):
Pharyngeal Pouches. The telopharyngeal body is being separated from the caudal pharyngeal complex, Le., from the third and fourth pouches (Bejdl and Politzer 1953).
Thyroid. In some instances the thyroid primordium may project into the pharynx as a “thyroid tubercle” (Politzer and Stockinger 1954; Politzer 1955; Orts-Llorca and Genis-Galvez 1958).
A thyroid primordium invaginating into the pharyngeal cavity was believed to be an abnormality different from the normal thyroid tubercle (Sgalitzer 1941).
Pancreas. The dorsal pancreas proliferates from the intestinal epithelium (Streeter 1942).
Stage 13 (ca. 4-6 mm; 30 or more pairs of somites; ca. 28 days):
Hypophysis. The basement membranes of the craniopharyngeal pouch and the brain are clearly in contact (O’Rahilly 1973).
Thymus. Weller (1933) recognized already a thymic primordium “ of considerable size” on the ventral part of the third pharyngeal pouch, whereas Norris (1938) considered this stage to be “‘preprimordial”’.
Thyroid. The median thyroid is now bilobed and is connected to the pharynx by a hollow pedicle (Weller 1933).
The telopharyngeal body has been regarded as a “lateral thyroid component”’ by some workers (e.g. Weller 1933).
Pancreas. The ventral pancreas may perhaps be distinguishable (Politzer 1952). 442 R. O’Rahilly
Stage 14 (ca. 5-7 mm; ca. 32 days):
Hypophysis. The craniopharyngeal pouch is prominent (Streeter 1945) and the notochord appears to be inserted into its dorsal wall.
The craniopharyngeal pouch has become elongated and blood vessels are beginning to grow in between the basement membranes of the pouch and brain (O’Rahilly 1973 a).
Epiphysis. A slight irregularity in the surface outline of the intact head corresponds to the future pineal body (O’Rahilly et al. 1982).
Thymus. Weller’s (1933) “thymus” (the third pharyngeal pouch) becomes elongated.
Parathyroids. “ Parathyrogenic zones” (Politzer and Hann 1935) are recognizable (Streeter 1945). The parathyroid 4 primordium has been illustrated at this stage by Weller (1933, Fig. 16).
Thyroid. The thyroid pedicle shows further elongation but is still connected to the epithelium of the pharynx (Weller 1933). Right and left lobes and an isthmus may perhaps be presaged (ibid.).
Suprarenal Cortex. A change in the characteristics of the cells of the coelomic epithelium appears between the mesogastrium and the lateral end of the mesonephros (Crowder 1957).
Suprarenal Medulla. The paravertebral sympathetic ganglia increase in size as a result of cell division and the addition of nerve fibres from the rami communicantes. The ganglia contain three types of cells: Mi, M2, and M3. The M3 cells are the “‘ parasympathetic cells” of Zuckerkandl (Crowder 1957).
Pancreas. The ventral pancreas (which may perhaps be distinguishable as early as stage 13) appears as an evagination from the bile duct at stages 14 (Blechschmidt 1973) and 15 (Streeter 1948). It is generally described as unpaired but, at least in some cases, may perhaps be bilobed (Odgers 1930) or even multiple (Delmas 1939).
Stage 15 (ca. 7-9 mm; ca. 33 days):
Epiphysis. The pineal body is detectable in the roof of the diencephalon (Stadium I of Turkewitsch 1933) (O’Rahilly 1968).
Thyroid. The thyroid primordium may be detached from the pharyngeal epithelium in some instances (Personal observations). “‘ At about the time” when the thyroglossal duct “becomes broken it loses its lumen” (Grosser 1912).
Suprarenal Cortex. The suprarenal primordium is first recognizable. A new type of cell (C1) from the coelomic epithelium is found in the subjacent mesenchyme. New cells (C2) appear in the medial wall of mesonephric gloDevelopment of Human Endocrine System 443
meruli and begin to migrate into the suprarenal primordium (Crowder 1957). Jirasek (1980) denies a mesonephric contribution to the suprarenal.
Suprarenal Medulla. All types of cells (M1, M2, and M3) increase in number. From stage 15 to stage 18, the suprarenal primordium is cigar-shaped and extends from segment T6 to segment L 1, lateral to the aorta and mesogastrium (Crowder 1957).
Stage 16 (ca. 8-11 mm; ca. 37 days):
Hypophysis. A slight indication of the infundibular recess may be seen in some embryos (O’Rahilly 1973 a).
Epiphysis. Cellular migration in an external direction occurs in the pineal body during stages 16 and 17 (Stadium 2 of Turkewitsch 1933) (O’Rahilly 1968).
Thymus. According to Norris (1938), “not until the primordium of the parathyroid [3] has been outlined can the remaining portion of the third pouch be recognized, by exclusion, as the primordium of the endodermal thymus”’.
Parathyroids. The parathyrogenic zones are closely related to the third and fourth aortic arches at 9 mm (Politzer and Hann 1935, unstaged embryo).
Parathyroid 3 is identifiable on the anterior wall of the third pharyngeal pouch (Weller 1933, Fig. 17) and “‘does not arise from a dorsal lobule”’ of the pouch (Norris 1937). The “sudden appearance of well-differentiated clear chief cells in the early primordia of the parathyroids’”’ at 9 mm was emphasized by Norris (1937).
Thyroid. The thyroid has lost its continuity with the pharynx and it consists of two lobes, an isthmus, and a remnant of the pedicle (Weller 1933).
Suprarenal Cortex. Another type of cell (C3) arises from the coelomic epithehum. Both C1 and C3 cells enter the suprarenal primordium. An ‘“‘enormous immigration” of C2 cells occurs (Crowder 1957).
Suprarenal Medulla. Cells of neural origin are migrating into the gland, separating the cortical cells into islands. Nerve fibres from the ganglia accompany the M1 and M3 cells. The M2 cells remain in the ganglia and become sympathetic ganglion cells (Crowder 1957).
Pancreas. The dorsal pancreas and the ventral pancreas are contiguous (Blechschmidt 1973).
Stage 17 (ca. 11-14 mm; ca. 41 days):
Hypophysis. The juxtacerebral wall of the craniopharyngeal pouch is the thicker. The lateral lobes (future infundibular, or tuberal, part) and the anterior chamber (Vorraum) are clearly visible (O’Rahilly 1973 a).
The infundibular recess displays a characteristically folded wall, namely the neurohypophysis (O’Rahilly 1973 a). 444 R. O’Rahilly
Thymus. The connection of the thymus with the pharynx has been severed (Weller 1933). The thymus is intimately approximated to the cervical duct (ibid.) According to Norris (1937), both third and fourth pouches make contact with the ectoderm, although only the third “‘receives an increment from the ectoderm”’.
Parathyroids. Parathyroid 4 is attached to the lateral surface of what Weller (1933) termed the “lateral thyroid component”
Thyroid. The lobes of the thyroid curve around the carotid arteries and are connected by a delicate isthmus. Lacunae “should not be confused with lumina of follicles”? (Weller 1933).
Suprarenal Cortex. The dorsal part of the whole suprarenal primordium is disorganized by the invasion of sympathetic nerves and cells, while the band of C2 cells and the coelomic epithelium remain intact (Crowder 1957).
Suprarenal Medulla. The first neural migration is at its height. Growth of the para-aortic complex is extensive. The plexiform complex is derived from paravertebral sympathetic ganglia T6-12 and usually L 1. Included in it are the primordia of the suprarenal medulla and of the celiac, superior mesenteric, and renal plexuses. Nerve fibres and “‘paraganglion”’ (M3) cells enter.
Pancreas. Ventral pancreas has now fused with dorsal (Streeter 1948). Perhaps the ventral and dorsal ducts have begun to blend (Russu and Vaida 1959).
Stage 18 (ca. 13-17 mm; ca. 44 days):
Epiphysis. Cellular migration in the pineal body forms a distinct “‘ anterior lobe” in which follicles appear (Stadium 3 of Turkewitsch 1933) (O’Rahilly 1973a). :
Thymus. The thymus makes contact with the thyroid gland and contains a series of canals internally (Weller 1933).
Thyroid. The median thyroid is in contact with “‘lateral thyroid components”? (Weller 1933) but others have maintained that the telopharyngeal body should not be regarded as a thyroid component (Bejdl and Politzer 1953).
The lobes of the thyroid are “composed of series of continuously communicating solid annectent bars” (Weller 1933). This is “the earliest stage of the definitive thyroid”’ (ibid.).
First differentiation occurs in Weller’s (1933) “lateral thyroid component,” which is beginning to “blend into uniformly constituted thyroid tissue”’.
Weller (1933) illustrated (Fig. 11) a thyroid gland that still showed continuity between its pedicle and the epithelium of the pharynx.
Suprarenal Cortex. The gland becomes reorganized. The C1, 2, and 3 cells form cords as sinusoids develop. Cells divide at or near the surface, where new cells are added (Crowder 1957). Development of Human Endocrine System 445
Stage 19 (ca. 16-19 mm; ca. 48 days):
Hypophysis. The caudal part of the craniopharyngeal pouch is reduced to a closed epithelial stem (Andersen et al. 1971).
Epiphysis. The “anterior lobe” of the pineal body shows a characteristic step and wedge appearance (Stadium 4 of Turkewitsch 1933) (O’Rahilly 1968).
Parathyroids. Parathyroids 3 become detached from the pharyngeal endoderm (Jirasek 1980).
Suprarenal Cortex. C2 cells lie on the surface of the gland and form a ‘capsule’? (Crowder 1957).
Suprarenal Medulla. Sympathicoblasts penetrate the cortex at stages 19 and 20, and form scattered islets of medullary tissue throughout the cortex (Jirasek 1980).
Stage 20 (ca. 18-22 mm; ca. 51 days):
Hypophysis. The adenohypophysial epithelium adjacent to the neurohypophysis constitutes the beginning pars intermedia (O’Rahilly 1973 a).
The walls of the craniopharyngeal pouch bud into the mesenchyme (Andersen et al. 1971; Jirasek 1980).
Thymus. The right and left components are in contact with each other (Weller 1933) but are “never completely fused”’ (Norris 1938, Siegler 1969).
Thymic cortex appears (in stages 20-22) as a result, according to Norris (1938), of migration of and covering by “cells derived from the cervical sinus”’.
Parathyroids. The parathyroid glands are attached to the lateral lobes of the thyroid (Weller 1933).
Weller (1933, Fig. 23) showed parathyroid 3 still rostral to parathyroid 4 at 23 mm, whereas (presumably due to variation in the “descent” of the thymus) Norris (1937, Fig. 4) showed parathyroid 3 rostral to, level with, and caudal to parathyroid 4 in embryos of 16-17 mm.
Thyroid. The “‘annectent bars” of the thyroid are more compact then previously (Weller 1933). The thyroid now exhibits its definitive external form (ibid.).
Stage 21 (ca. 22-24 mm; ca. 52 days):
Hypophysis. The pharyngeal stalk becomes fragmented (Jirasek 1980).
Parathyroids. Failure of descent of the third complex (parathyroid and thymus) on the left side has been recorded (Norris 1937, Fig. 6).
Suprarenal Cortex. The cellular “capsule” becomes covered by a layer of fibrous tissue (Crowder 1957). 446 R. O’Rahilly
Stage 22 (ca. 23-28 mm; ca. 54 days):
Parathyroids. Parathyroids 4 become detached from the pharyngeal endoderm (Jirasek 1980).
Suprarenal Cortex. The C2 cells have changed and resemble fibrocytes (Crowder 1957).
Stage 23 (ca. 27-31 mm; ca. 57 days):
Hypophysis. Canaliculi, 1.e., extensions of the original lumen of the craniopharyngeal pouch, are formed in the buds that extend into the mesenchyme (Andersen et al. 1971).
Epiphysis. The pineal body has reached Stadium 5 of Turkewitsch (1933) (O’Rahilly 1968).
Thymus. The cortex is well-developed, “true lobulation’’ has begun with the appearance of “fine superficial scallops,” lymphocytes are present sparse ly in the subcortical zone, and vessels are found within the thymus (Norris 1938). ,
Suprarenal Cortex. It appears that C2 cells first enter the body of the gland at this stage. The pattern of the arterial supply is established. The cellular “capsule” is penetrated by arterial capillaries which join the sinusoids. Their points of entry give the surface of the gland an appearance of cobblestones. The zona glomerulosa is formed of C1 and C3 cells. Cells from this zone and from the “capsule” migrate centrally into the cords (Crowder 1957).
Suprarenal Medulla. Nerve fibres and neuroblasts are first seen in the body of the gland. The paraganglion (M3) cells are beginning to multiply rapidly and, from 30 mm (stage 23) until birth, some are differentiating into chromaffin cells (Crowder 1957).
Discussion
It becomes clear from this survey that (1) much more precise information on early development is available than would be gleaned from a glance at works on endocrinology, (2) nevertheless many gaps remain to be filled, and (3) a number of points continue to be controversial, ¢.g., the early development of the pharyngeal region and the thyroid gland.
Because only staged embryos have been considered in this study, it has not been possible to include much otherwise valuable information, e.g., ultrastructural observations of the cells of the suprarenal cortex (Fujita and Jhara 1973).
Hypophysis cerebri ( Pituitary Gland). It is clear from the graphic reconstructions of stage 10 by Bartelmez and Evans (1926) that the future adenohypophysis and neurohypophysis develop in close association and do not have to grow towards each other, as is so frequently and incorrectly stated. As Gilbert (1935) pointed out, the mammalian hypophysis “arises as a single structure.” Development of Human Endocrine System 447
With regard to the prenatal functional activity of the endocrine glands, it has been maintained that “‘the differentiation of the hormone-active cells, with a few exceptions such as the diencephalon, begins at an early stage together with the anlage of the organ” (Merker 1974). When the hypophysis and diencephalon become functionally active at about the middle of prenatal life, the fetus is capable of regulating its own endocrine system and, according to morphological findings, the fetus of “‘the second half of pregnancy thus appears to be largely autonomous” (ibid.).
Epiphysis cerebri (Pineal body). An important but frequently neglected account of pineal development in the human was published by Turkewitsch (1933). Ten stages of pineal differentiation were proposed from 6mm to more than 300 mm. The first five of these, based on an examination of more than twenty embryos, involved the embryonic period proper, and an attempt to relate these to Carnegie stages was made by O’Rahilly (1968).
Pharyngeal Pouches. For reasons explained by Frazer (1923) and emphasized by O’Rahilly (1973b) and by O’Rahilly and Tucker (1973), the “fishy nomenclature” involved in the term “branchial” is not appropriate to mammals. The better term pharyngeal pouch is used here.
The telopharyngeal body (so-called “‘ulttmobranchial body” or “fifth pharyngeal pouch’’) has been the subject of numerous discussions, e.g., by Kingsbury (1939), Sugryama et al. (1959), and Sugiyama (1971). Wells (1933) preferred the term “lateral thyroid component” whereas Norris (1937) saw “no reason for retaining”’ such terms as ultimobranchial body and caudal pharyngeal complex. The term telopharyngeal body (O’Rahilly and Tucker, 1973) will be employed here and this structure, together with the fourth and third pharyngeal pouches, constitutes the caudal pharyngeal complex illustrated by Bejdl and Politzer (1953, Figs. 3 and 4).
Thymus. The question of a thymus 4 has been discussed by many authors. (See Cordier and Haumont, 1980, for a recent account in the mouse.) In the human a thymus 4 was found by neither Weller (1933) nor Norris (1938) but its existence, at least as an inconstant structure, was claimed by Gilmour (1937) and Van Dyke (1941). The last-named author found a thymus 4 in 42 per cent of fetuses from 14 weeks to birth. Another controversial point, namely “the in situ epithelial versus the extrathymic derivation of the initial population of lymphocytes in the embryonic thymus” (Ackerman and Hostetler 1970) may be subject to species differences. Thymic (Hassall’s) corpuscles do not appear until the fetal period.
Parathyroid Glands. The parathyroid glands were perhaps the last major structures visible to the unaided eye to be discovered during the nineteenth century (O’Rahilly 1982). There appear to be always at least four parathyroid glands present during human development, and occasionally five or six may be found (Boyd 1950). By 150 mm C.-R., several different types of cells are distinguishable in the fetal parathyroid glands (ibid.). 448 | R. O’Rahilly
Medulla Fetal Permanent Cortex Cortex M1, M3 Fasciculo- Z. reticularis reticular M2 vi Z. fasciculata @ Fetal Postperiod natally Sympathetic eo ° NN & celts Z. gtomerulosa @ Co Capsule Cortical primordium | Fig. 1. Diagram to show Crowder’s (1957) interpretation of the development (5) C2 of the suprarenal gland. The scheme should be read from below upwards. The C1 C3 (15) cell types in the cortex are numbered C7, C2 and C3: those in the medulla are Mesonephric marked M1, M2, and M3. The numerals Coelomic epithelium epithelium within circles indicate embryonic stages
Thyroid Gland. It has been shown that synthesis of immunoreactive thyroglobulin is already established by 6.4 mm C.-R. (Gitlin and Biasucci 1969). Follicles were claimed to be present in an unstaged embryo of 14 mm (Taki 1958), and “primitive” and “‘transitional” follicles were found by Sugiyama (1971) from 14 to 48 mm. Traces of secretory (“precolloidal’’) substance may be found in “transitional follicles’? from 32 mm onwards (Taki 1958). Actual colloid “could not be demonstrated” in fetuses less than 60 mm C.-R. (Lietz et al. 1971) and the “early colloid production period” extends from 65 to 80 mm (Shepard et al. 1964).
It is now generally maintained that the C-cells of the thyroid gland are derived from the neural crest and become incorporated in the thyroid by way of the telopharyngeal body. The implications of this concept to pathology have been discussed by Roediger (1974). Parafollicular or C-cells in an immature condition can be identified by electron microscopy in fetuses of 50 mm (Chan and Conen 1971) to 120 mm C.-R. (Lietz et al. 1971).
Suprarenal Gland. The important study of Crowder (1957) provides the — only detailed account of the suprarenal gland in staged human embryos. Further data are given by Jirasek (1980). Contributions to our knowledge of the fetal period have been made by Sucheston and Cannon (1968) among others. Apart from a temporary and “‘ill-defined fascicular zone”’ at 50-60 mm, the zona fasciculata and zona reticularis do not appear until after birth (Crowder 1957). Jirasek, however, speaks of a “fetal fasciculata” and a ‘“‘fetal reticularis” during “the third month” of fetal life. In the late embryo and fetus, the part of the cortex deep to the zona glomerulosa “is now, by general usage, called the feta/ cortex”’ (Crowder 1957). It degenerates after birth but it should be “understood that the ‘fetal cortex’ is Development of Human Endocrine System 449
composed of cells derived from the same sources as the ‘ permanent cortex’”’, 1.e., from cells in the “capsule” and zona glomerulosa {ibid.). According to Jirasek (1980), ““the subcapsular layer of blastematous cells” differentiates “during the fourth month” of fetal life into “the primordium of the definitive adrenal cortex.”
Crowder’s (1957) interpretation of the development of the suprarenal gland is summarized in Fig. 1.
Pancreas. The dorsal pancreas appears first and there is some doubt as to the precise stage at which the ventral component is first detectable. The islets are distinguishable at the junction between embryonic and fetal peri- » ods: 7-8 weeks (Liu and Potter 1962) or 9-10 weeks (Jirasek 1965; Like and Orci 1972). Pearse (1903) did not observe islets at stage 23 but found them at 54mm C.-R. Ferner and Stoeckenius (1951) detected islets in their youngest specimen: 130 mm C.-H.
The details of a simple model to illustrate the development of the pancreas in relation to the adult structure of the organ have been published recently (O’Rahilly and Miller 1978).
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Accepted December 12, 1982
