Paper - The development of the mammalian pituitary and its morphological significance (1908)

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Herring PT. The development of the mammalian pituitary and its morphological significance. (1908) Quar. Jour. Ex. Physiol. 1: 161-185.

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This historic 1908 paper by Herring describes the development of the pituitary. The histological structures identified in the posterior pituitary are named after this author, "Herring Bodies".


See also by his author - Herring PT. The histological appearances of the mammalian pituitary body. (1908) Quar. Jour. Ex. Physiol. 1: 121-159.

Modern Notes: pituitary | cat

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1903 Islets of Langerhans | 1903 Pig Adrenal | 1904 interstitial Cells | 1908 Pancreas Different Species | 1908 Pituitary | 1908 Pituitary histology | 1911 Rathke's pouch | 1912 Suprarenal Bodies | 1914 Suprarenal Organs | 1915 Pharynx | 1916 Thyroid | 1918 Rabbit Hypophysis | 1920 Adrenal | 1935 Mammalian Hypophysis | 1926 Human Hypophysis | 1927 Adrenal | 1927 Hypophyseal fossa | 1930 Adrenal | 1932 Pineal Gland and Cysts | 1935 Hypophysis | 1935 Pineal | 1937 Pineal | 1935 Parathyroid | 1940 Adrenal | 1941 Thyroid | 1950 Thyroid Parathyroid Thymus | 1957 Adrenal
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The Development of the Mammalian Pituitary and its Morphological Significance

By P. T. Herring

From the Physiology Department, University of Edinburgh

Received for publication 11th February 1908

Introduction

The development of the pituitary body has been a favourite subject of research by embryologists. Its position in the embryo, forming as it were a meeting-point for the anterior end of the neural canal, buccal invagination, archénteron, and notochord, gives to the pituitary an importance, the significance of which has been the object of much speculation. Some authorities have looked upon its relations to these structures as more or less accidental; others have attached great Weight to them. Kupffer, indeed, regarded the pituitary body as an important key to the phylogeny of the vertebrate head. The morphological significance of the pituitary is also of interest from a physiological point of view, and some of the theories which have been advanced regarding it will be briefly discussed in this paper.


Nearly all the work that has been done on the development of the pituitary body has been concerned with its mode of origin and with the early stages of its growth. The later stages, although probably of greater physiological importance, have been comparatively neglected. The differentiation of the epithelium of the anterior lobe, the relations of epithelium to the nervous tissue of the posterior lobe, and the extraordinary differences in the vascularity of its several parts are all features which need investigation. Its development in mammals has been followed chiefly in animals in which the posterior lobe of the pituitary becomes a solid structure at a comparatively early stage. In the cat, this lobe remains hollow throughout development, and presents peculiarities of morphological interest which are not found in the pituitaries of other animals. The structure of the posterior lobe in the cat is also of a simpler character, and the nature and arrangement of the cells found in it can be interpreted more readily than in the case of those animals which possess a solid lobe. For these reasons the pituitary body of the cat forms the basis of the description in this paper. The embryos of man, ox, and pig, which furnish a different type of pituitary, have also been eizamined, and some of the more important features presented by them receive attention.

Historical

The pituitary body was at one time thought to be wholly derived from the brain, but Rathke (26) in 1838 described the invagination of mucous membrane which is now known as Rathke’s pouch. Rathke rightly assigned to this pouch the origin of the epithelial portion of the pituitary, but was mistaken in believing it to be derived from the entoderm of the fore-gut. His view was not at once accepted. Reichert (28) failed to find the invagination, and put forward the theory that the epithelial portion of the pituitary is a structure of mesodermic origin derived from the anterior end of the notochord. His (14) lent additional support to Reichert’s view, but made no special investigations of the subject himself. Both Rathke (27) and Reichert (29) subsequently changed their opinions, the latter believing the anterior lobe to arise from a proliferation of the cells of the pia mater. Dursy (8) sought to unite the original view of Rathke with that of Reichert and His, and described the origin of the epithelium of the pituitary from the fore—gut, and the origin of its vascular stroma from the tissue of the head of the notochord. W. Miiller (23) demonstrated that the anterior lobe of the pituitary is derived from Rathke’s pouch, but fell into the same error as Rathke and Dursy in believing it to be of entodermic origin. The later researches of Gotte (12) and Balfour (3) showed that the pouch described by Rathke is derived, not from the fore-gut, but from the epithelium of the buccal cavity immediately in front of the oral plate. The pouch is now recognised as an ectodermic structure.


The posterior lobe of the pituitary was at first believed to represent the anterior extremity of the brain (v. Baer (2)). Gotte (12) showed that in amphibians this is not the case, the infundibulum being a later formation. The researches of Mihalkovics (21), van Wijhe (35), Kupffer (20), and others have demonstrated that the infundibulum cannot be regarded as the representative of the anterior end of the brain axis; it is an outgrowth of the “ Zwischenhirn ” or thalamencephalon.


The proximity of the anterior end of the notochord to the developing pituitary body led to the belief, not only that the notochord enters into the structure of the pituitary, but that it also exercises a mechanical influence upon the formation of the infundibulum. Both His and Dursy considered that a close union between the notochord and the wall of the cerebral vesicle is the dominating factor in the development of the infundibulum, but were not agreed as to the exact manner in which this is brought about. W. Muller believed that the head of the notochord anchors a portion of the wall of the brain, and that with the growth of the surrounding tissues the rest of the brain is carried forwards, leaving a diverticulum of its wall, the infundibulum, attached to the notochord. The attachment is subsequently dissolved by a proliferation of connective tissue cells. Mihalkovics (21) and others showed that the head of the notochord does not come into immediate relationship with the brain, and cannot therefore act upon it in this manner.


The most complete account of the early development of the pituitary body is that given by Mihalkovics (21), who investigated the subject in rabbit and chick embryos. Mihalkovics found that the anterior lobe is developed from Rathke’s pouch, which, in mammals as in amphibians, is of ectodermic origin. The beginning of the pouch or hypophysial angle lies in front of the oral plate, Where the epidermis bends round the base of the brain to the nasal mucosa. In the rabbit, Mihalkovics states that the end of the notochord is in contact with the epidermis at the back of Rathke’s pouch. When the oral plate ruptures, its upper stump, containing in its upper part the head of the notochord, bends forward and narrows the mouth of the epithelial pouch, leading to the formation of a definite sac—the hypophysial sac. The wall of the sac presses upon the base of the anterior brain vesicle, giving rise at its upper extremity to a fold in the wall of the brain which becomes the primitive infundibulum. Mihalkovics denied that the end of the notochord is ever united to the wall of the fore-brain; it does not enter into the formation of the infundibulum at all, but has some influence upon the hypophysial sac, by preventing this from extending backwards. The primitive infundibular process comprises the surrounding tissue of the tuber cinereum as well as the origin of the infundibulum, and the true infundibulum is formed at a later stage by its own growth from a portion of the primitive infundibular process. Mihalkovics made a careful investigation of the relations of the notochord, and found that its head touches the lower part of the posterior wall of the hypophysial sac in rabbits, but is placed at a higher level in birds; it exercises no traction upon the sac in either, and, beyond presenting a barrier to the backward growth of the sac, takes no part in the formation of the pituitary body.


The main conclusions of Mihalkovics’ researches have been cofirmed by Kolliker (16), Kraushaar (18), Minot (22), Kupffer (19), Salzer (33), and others. Kupffer described an additional origin of part of the anterior lobe of the pituitary from the entoderm of the fore-gut. According to Kupffer, the pituitary body of amphibians is built up from three separate sources: part of the epithelial lobe is derived from Rathke’s pouch, and part from the anterior end of the fore-gut, while the infundibulum is of brain origin. In mammals, e. g. the sheep, the hypophysial pouch appears behind the “ Riechplakode.” Behind this and ventral to it is a swelling, the “Haftscheibe,” which is an important larval organ in Lepidosteus. Then comes the double-layered oral plate (“ Rachenh ant”), and behind this an outgrowth of entoderm directed dorsally and forwards, known as Seessel’s pouch. The third portion of the pituitary, the cerebral, appears later, after the disappearance of the oral plate and median “Riechplakode.” In the next stage the growth of entoderm increases, but is cut off from Seessel’s pouch; no cavity is to be found in it, and the end of the notochord remains in contact with it. The infundibulum now to grow. In the older embryos, e. g. 11—mm. sheep, the entodermic part degenerates and appears as a string-like appendage of the notochord; it eventually disappears, and does not enter into the formation of the adult mammalian pituitary.


Kupffer came to the conclusion that the intimate relationship between infundibulum, mouth, and intestine is not an accidental one, but denotes an ancestral communication between the brain tube and the anterior part of the intestinal canal. A structure resembling in many respects the early stages of development of the vertebrate pituitary is found in Ascidians, and is known as the subneural gland. J ulin (15) in 1881 pointed out that this gland is probably homologous with the hypophysis of higher vertebrates, and since then it has been frequently spoken of as the Ascidian hypophysis. Kupffer believes that the direct ancestors of vertebrates showed the same relations as are seen to—day in the tailed Ascidian larva. In a scheme of the ancestral vertebrate he describes the mouth (“ Palaeostoma ”) opening dorsally in front of the brain. The brain tube is in communication with the anterior part of the intestine by a canal running through the base of the anterior brain vesicle. This canal has developed upon it a subcerebral gland. Ventral to the palaeostoma is the “ Haftorgan ” on the anterior pole of the body. In the course of development the new vertebrate mouth (Neostoma) is formed, in agreement with Dohrn’s hypothesis, from a pair of gill-clefts below the “Haftorgan.” The part of the intestine between the old and the new mouth, or preoral intestine, is reduced, but persists to a certain extent in some vertebrates. The palaeostoma is lined by epidermis, and its representative in vertebrates is Rathke’s pouch; it also forms the outer part of the nasal duct (“ Nasenrachengang ”) of Myxine, and the entire nasal duct of Petromyzon. The remains of the canalis neurentericus anterior, with its appertaining glands, are to be seen in the infundibular process and saccus vasculosus. In mammals, the only representative of the preoral intestine is the transitory appearance of the solid mass of cells formed from Seessel’s pouch, but in amphibians it persists as part of the anterior lobe of the pituitary.


Kupffer’s views on the morphological significance of the pituitary body have not met with general acceptance. Willey (36) states that the present relation of the hypophysis to the infundibulum in the craniates, however intimate it may be in some cases, is, nevertheless, incidental and secondary. Willey believes that the hypophysis arose in connection with a functional neuropore. B. Haller (13) criticises Kupf f er’s results and differs from him in many important particulars. He believes the nasal duct of Cyclostomata to be a secondary structure and not related to the origin of the hypophysis. He also states that the anterior lobe of the pituitary of mammals and other vertebrates is a tubular gland which pours a secretion into the subdural space. The latter statement has not been confirmed by subsequent observers. Gaskell (9) quotes Haller’s results in support of the theory that the glandular hypophysis was originally the coxal gland of Arthropoda.


Kupffer’s description of the threefold origin of the pituitary body has received support from observations by J. Nusbaum (24) and SaintRemy (31). Nusbaum found that in dog embryos of 9 mm. Seessel’s pouch is well developed, and its anterior extremity abuts against the posterior wall of Rathke’s pouch. In 80 per cent. of older embryos examined it gives rise to a column of cells which unites with the epithelium of Rathke’s pouch, and thus enters into the formation of the anterior lobe. In the remaining embryos no such appearance is seen, and the anterior lobe is entirely ectodermic in origin. Traces of a lumen were noticed by Nusbaum in the column of cells growing from the fore-gut, but not a definite communication between the interior of the buccal invagination and the fore-gut. The connection is not preserved for long, and the entodermic cells disappear, with the exception of a few which join the posterior wall of Rathke’s pouch. What further part these cells play—if any—in the formation of the anterior lobe of the pituitary Nusbaum did not determine.


Saint—Remy (31) described a budding of Seessel’s pouch in the embryo chick towards the seventieth hour of incubation. The bud acquires a fine lumen, and, reaching Rathke’s pouch, affords a direct communication between the interior of the latter and the fore-gut. The connection lasts a little, then disappears, the cells of Seessel’s pouch never actually uniting with those of Rathke’s pouch. Saint-Remy agrees with Kupffer that the entodermic origin is rudimentary in birds and mammals, and does not enter into the formation of the adult pituitary body. It is, however, of morphological importance, and betokens the existence in lower forms of vertebrates of a communication between the intestine and the buccal invagination.


Dohrn (7) looked upon the pituitary as the remains of a preoral gillcleft. Salvi (32) has brought forward evidence in support of this View, and states that in reptiles part of the pituitary is developed from the walls of the premandibular cavities, which he believes to be the representatives of gill-clefts. Valenti (34) describes the origin of the anterior lobe in amphibians from an invagination of the fore—gut arising some distance behind Seessel’s pouch. The invagination, he considers, has not the significance attributed by Kupf fer to Seessel’s pouch, but is rather to be regarded as the representative of a gill-cleft. Valenti therefore supports Dohrn’s theory. Dohrn’s View was based chiefly upon the assumption of a bilateral origin of the anterior lobe of the pituitary. Dohrn himself described a bilateral origin in Hippocampus, and Gaupp (10) found something similar in reptiles. Gaupp, however, described a median origin in addition to lateral ones, and believes all to be formed from the buccal cavity.


Yet another interpretation of the significance of the pituitary has been put forward by Beard (4), who believes the anterior lobe to be homologous with the permanent mouth of Annelids.

Author's Observations

My own results are confirmatory of those of Mihalkovics and Kupffer. In a 4 mm cat embryo, the youngest I have had the opportunity of examining, the appearance is that indicated in fig. 1. The oral plate (f) between buccal invagination and fore-gut has just ruptured. Immediately in front of the oral plate is the hypophysial angle described by Mihalkovics. The anterior limb of the angle is composed of buccal epithelium, which in this situation is closely adherent to the wall of the anterior cerebral vesicle. The posterior limb of the angle, also composed of buccal epithelium, leaves the wall of the brain and bends downward to form the anterior layer of the upper stump of the oral plate. Atthisstage there is no invagination of the wall of the cerebral vesicle to form the infundibulum, but its site is indicated by a definite depression. The anterior end of the notochord does not touch the posterior limb of the hypophysial angle, but is separated from it by a large blood-channel (0). Behind the oral plate is a small dorsal invagination of the wall of the fore-gut, which is the only indication of anything resembling Seessel’s pouch. Its wall is not thickened, and there is no evidence of any entodermic origin for the pituitary in this specimen.


Fig. 1. Mesial sagittal section through head of 4 mm kitten. (Diagram.) a, hypophyaial angle formed by buccal mucous membrane; b, depression in wall of cerebral vesicle where the intundibulum is formed; c, blood-channel; d, anterior end of lore-gut or Seessers pouch; e, head of nctochord ; 1', upper stump of ruptured oral place.


Fig. 2. Mesial sagittal section through part of head of a. 6 mm kitten. a, buccal lnvaglnatlon or Bsthl-re’: pouch; b, beglnnlng of lnvsginatlon of well of cerebral vesicle to form the lnlundlbulnr process; 4:, blood-channel; d, clump of cells derlved from anterior and of tore-gut; 9, head of notochord.


In a 6 mm cat embryo (fig. 2), the remains of the oral plate have disappeared. The hypophysial angle has become a definite sac (a), Rathke’s pouch. This change appears to have been brought about by a bending forwards of the upper stump of the oral plate and a proliferation of the cells in its wall. The pouch is Widening out behind the neck, and the latter is found to be constricted when the sections next in series to it are examined. The anterior wall of Rathke’s pouch is closely applied to the Wall of the cerebral vesicle, and at the dorsal extremity of the pouch an invagination of the wall of the cerebral vesicle is forming the primitive infundibulum.


The head of the notochord bears no immediate relation to Rathke’s pouch, and is separated from it by a clump of cells which is continuous with the epithelium of the fore-gut, and appears to be formed by a proliferation of the cells of the latter. A large blood-vessel (c) is also seen in this specimen, lying between Rathke’s pouch and the head of the notochord.


At this stage it is difficult to determine where ectoderm ends and entoderm begins; the upper stump of the oral plate has disappeared as such, and its representative is uncertain. There is no indication of a pouch in the fore-gut, but the clump of cells appears to be derived from the wall of the latter. Minot (22) makes the fold of epithelium at the posterior margin of Rathke’s pouch homologous with the upper lip of Petromyzon. If this is the case, the fore-gut must begin behind this fold. The close relation between the head of the notochord and the cell clump makes it likely that the latter is derived from the fore-gut, for, in the 4«-mm. embryo, the head of the notochord is some distance behind the oral plate, and the epithelium opposite it is that of the fore-gut. The clump of cells is the only structure which resembles the proliferation of entoderm described by Kupffer. It is not found in any of the older embryos that I have examined, but the amount of suitable material at disposal for this purpose has been limited. Rathke’s pouch is the only part that enters into the formation of the anterior lobe of the pituitary; it is single and median in origin, and there is no indication in the embryos of the cat and the pig of any other “Anlage” for the anterior lobe. I have not found any communication between the epithelium of Rathke’s pouch and that derived from the foregut, as described by Nusbaum in the dog, but cannot say that this does not occur. In the specimens I have examined there is nothing to indicate in the slightest degree that Rathke’s pouch is reinforced by epithelium from the fore-gut. The epithelial proliferation of the latter disappears as stated by Kupffer, and takes no part in the formation of the pituitary.


One of the most important characteristics of the developing pituitary is the close union maintained between buccal and cerebral portions from the earliest stage. Minot (22) emphasised its importance in mechanically keeping the two parts together, and thus explaining their intimate relations. Salzer (33) also noted it, and states that he could find no connective tissue between the infundibular process and hypophysial sac. With these observations I thoroughly agree. The buccal epithelium in the anterior part of the hypophysial angle is intimately connected with the epithelium of the cerebral vesicle, without the interposition of connective tissue. In the further growth of the embryo this close union is preserved, but in other parts connective tissue develops and separates the buccal epithelium from the wall of the cerebral vesicle. N o doubt this process is contributory to the formation of Rathke’s pouch and infundibulum, but it is probably of morphological significance as well, and betokens the existence in an ancestral vertebrate of a communication between buccal cavity and neural canal.


A later stage of development is shown in fig. 3, which is taken from a pig embryo of 12 mm. The buccal mucous membrane is now widely separated from the wall of the cerebral vesicle, except at that part Where the anterior wall of Rathke’s pouch closely adheres to it. The infundibulum is only beginning to form, and the cells lining the cerebral vesicle at this point have proliferated and elongated, and look more like ependyma cells. There is no indication of any proliferation of cells of the fore—gut. Rathke’s pouch is median in situation, its neck is constricted, and serial sections show that there is no lateral origin of the pituitary. The notochord persists, but has no immediate relation to Rathke’s pouch. It takes no part mechanically or otherwise in the formation of the pituitary. Its situation, nevertheless, is not without significance; its arrest behind the anterior end of the brain tube allows the latter to communicate with the buccal epithelium and possibly with the fore—gut in some animals. Had the notochord grown further forward, a median origin for the anterior lobe of the pituitary would have been impossible. The median origin of the pituitary, or rather the ancestral condition which this implies, may indeed explain why the head of the notochord has been arrested in this situation.


Fig. 3. Mesial sagittal section through part of head of a 12 mm pig embryo. a, Rathke’s pouch ; b, beginning of infundibular process; 2, blood-channel ; d, remnant of Seessel's pouch (7); e, notochord.


Fig. 4. Mesisl sagittal section through part of head of an 18 mm kitten. a, hypophysial sac now closed below; b, lntundibular process; g, neck of sac connected with nasal mucous membrane; h, cartilage of sphenoid bone.



In an 18 mm cat embryo considerable changes have taken place (fig. 4). Rathke’s pouch has become a closed sac, but its wall is still connected by a stalk of epithelium with what is now becoming nasal mucous membrane.


The narrowing of the neck of the sac, its closure and ultimate disappearance are due to the strong growth of connective tissue around it and the development of the sphenoid bone. It is unnecessary to attribute the change to the pressure exerted on the neck of the sac by the carotid arteries and their growing adventitia, as did W. Miiller. The above explanation of Mihalkovics is probably the right one. The hypophysial sac is now of considerable size and extends laterally, its anterior wall being still in close connection with the wall of the cerebral vesicle. A well-marked invagination of the wall of the latter constitutes the infundibular process ; its anterior wall is also closely invested by the epithelium of the wall of the hypophysial sac. ' The infundibular process becomes the nervous portion of the posterior lobe of the pituitary, while the part of the wall of the hypophysial sac adhering to it constitutes the epithelial covering of the posterior lobe or “Epithelsaum” of Lothringer. Epithelium and nervous tissue have been in close contact with one another from their first appearance. The cavity of Rathke’s pouch persists throughout life as the epithelial cleft which partly separates the anterior from the posterior lobe. In its lateral extension the sac is beginning to envelop the sides of the infundibular process. Its walls are composed of cylindrical cells which closely resemble those of the infundibular, process. They are thickened in the anterior part of the sac in the region of its neck, where there is a distinct fold; the thickening in this situation is the beginning of the anterior lobe proper of the pituitary. Its cells are not as yet differentiated from the cells of the remainder of the sac.


During subsequent development the pituitary body is removed further and further from the nasal mucosa by the growth of the sphenoid bone. Ossification in the latter is delayed for some time by the persistence of a cord of epithelial cells connecting the anterior lobe of the pituitary with the nasal mucous membrane. This connection is still found in cat embryos of from 35 to 40 mm., butis then imperfect and soon after disappears, allowing the opening in the bone to close up. Differentiation between anterior lobe proper and the pars intermedia now begins to take place. The anterior lobe is formed by a proliferation of the cells of the lower part of the anterior wall of the sac just above its neck. Solid columns of cells are formed in this situation, and invade the cavity of the sac so as gradually to fill it, leaving only a narrow space or cleft between them and the epithelium covering the posterior lobe. The anterior lobe also grows forward and laterally. The neck of the sac retains a tubular character for some time, and becomes somewhat convoluted. One of these convolutions (fig. 5, la) applies itself to the under surface of the brain and gives rise to the tongue shaped process which extends forwards from the anterior lobe towards the optic chiasma.


The structures which enter into the formation of the pituitary are closely related to large blood-vessels from their earliest appearance. In figs. 1 and 2 a large blood-channel is seen lying immediately behind Rathkeis pouch, in front of the notochord. Dursy, indeed, as already stated, sought to derive the origin of the blood-vessels of the pituitary from the tissue of the head of the notochord. The exact manner in which the blood-vessels of the anterior lobe of the cat's pituitary are formed is somewhat difficult to make out, but in the pig embryo their origin is partly sinusoidal. The cell columns of the anterior lobe grow into large blood sinuses, pushing the endothelial fining before them. In a pig embryo of 60 mm. the appearance of the anterior lobe is very like that of the developing liver. It is not, however, entirely sinusoidal, and some ingrowth of blood-vessels with accompanying connective tissue takes place, the latter being always small in quantity. This method of development of the bloodvessels of the anterior lobe was first pointed out by Gaupp (10) in reptiles.


Fig. 5. Mesial sagittal section through part of head of 35 mm kitten. a, remains of cavity of Rathke’s pouch now recognisable es the epithelial cleft of the pituitary ; b central cavit of inlundibulsr process; g, remnant of epithelial duct connecting hypophysisl sac wit the nasal mucous membrane; i, third ventricle 0! brain; k, part of epithelial duct which becomes the tongue-like process of pars intermedia; l, cells of anterior wall of hypopliynisl sac (pars iutermedis); m, anterior lobe proper; n, vascular knob covered with ependyms cells projecting into cavity of the infundibular process.


Gaupp found large blood-spaces of a venous nature, and states that the epithelium grows into them, passing through their walls. Minot also inferred from the structure of the anterior lobe of the pituitary that the development of its blood-vessels is partly sinusoidal. While the anterior lobe and tongue-like process of epithelium are extremely vascular, that part of the wall of the original sac which is applied to the brain remains devoid of blood-vessels. Its cells proliferate and spread round the nervous substance of the posterior lobe, forming a covering of epithelium of varying thickness.


The nervous portion of the posterior lobe has meanwhile grown in length and expanded to form a definite body, which, in the cat, retains a large central cavity. The neck is constricted, but remains hollow. In a 35-mm. cat embryo (fig. 5) the epithelium lining the central cavity is composed of ependyma cells with thin processes, the nervous tissue is small in amount, contains few cells, and is chiefly made up of the processes of the lining cells. At the postero-superior angle of the lobe there is frequently seen a knob-shaped body (n) of large and deeply staining ependyma cells, behind which are blood-vessels. This vascular knob appears to be growing into the central cavity, and marks the entry of blood-vessels into the posterior lobe. The thickening of epithelium does not persist, but disappears; the blood-vessels, however, grow into the lobe in this situation. The appearance is not a constant one, but When it occurs the deeper staining of the ependyma cells and the vascularity of the tissue behind them are striking , features. The blood-vessels of the posterior lobe of the pituitary are, in the cat, almost entirely derived from an ingrowth in this situation; true capillaries are formed in the lobe and are accompanied by a small amount of connective tissue. The latter is never present in large quantities, and the posterior lobe of the pituitary does not become a connective tissue appendage of the brain, as stated by W. Muller and many others; there is remarkably little connective tissue in the posterior lobe. The appearance which W. Muller likened to a spindle-celled sarcoma is very marked in the older pituitary. It is, however, not due to the presence of connective tissue fibres and cells, for when the pituitary is prepared by Cajal’s silver method it is found that theappearances described by W. Miiller are caused by the presence of large numbers of ependyma- and neuroglia-cells and fibres, chiefly the former. In the developing pituitary there is never any sign of true nerve cells. The ependyma cells lining its central cavity are at first like those lining the third ventricle of the brain. Their fibres run vertically and end at the outer surface of the lobe. As the posterior lobe elongates the peripheral ends of the fibres remain attached, the cells become more numerous, and are moved further and further from the points of attachment of their fibres. In this way the ependyma fibres of the neck of the posterior lobe acquire an oblique direction, and finally run almost longitudinally, their cells of origin being situated much further back than the outer ends of their fibres. In the posterior lobe of the kitten, especially in the region of the neck, the ependyma fibres become very numerous, and their arrangement, as shown by Cajal’s method, is very complex. In the adult cat the individual fibres are much thicker, and the cells fewer in proportion to the size of the lobe. Neither by Cajal’s nor Golgi’s method have I been able to find true nerve fibres entering the posterior lobe of the cat’s pituitary through the neck. The ependyma fibres take on a lighter stain by Cajal’s method than the nerve fibres in the brain. Fibres can be seen in the" fully developed pituitary which are thinner and stain more deeply. Some of them enter the epithelium round the neck of the posterior lobe and ramify there. They are probably true nerve fibres which have entered with the blood-vessels, and, as Berkley (5) states, derived from the sympathetic.


Herring1908b fig06.jpg


Fig. 6. Mesial sagittal section through developing pituitary body of a human foetus (fifth month). Drawing from a photograph. a, optic chiasm; b, tongue-like recess of epithelium; c, third ventricle; d, anterior lobe; e, neck of posterior lobe , f, epithelium surrounding neck; g, epithelial cleft; h, posterior lobe.


In the embryos of man, ox, and pig the posterior lobe is solid from an early stage, and is relatively smaller than the anterior lobe. There is the same close connection between the epithelium and the nervous tissue. In fig. 6 a mesial sagittal section through the pituitary body of a human embryo (5th month) is illustrated. The anterior lobe is a compact structure of columns of epithelial cells devoid of lumina. Many of its cells are granular in character, and are beginning to differ from the clearer cells, which are in closer relation with the nervous tissue. There is a wellmarked cleft in the epithelium, Which, in this specimen, is carried right round the neck of the posterior lobe. The cells of the pars intermedia, or that portion of epithelium derived from the anterior Wall of Rathke’s pouch, which is closely adherent to the wall of the cerebral vesicle, are widely spread over the surface of the neck and body of the posterior lobe; they also tend to break up the neck of the lobe by passing into its substance along with blood-vessels, and extend forwards in a. thin layer for some distance over the tuber cinereum. Fig. 7 shows the appearances presented by the same pituitary in a section further from the middle line. The anterior lobe is rather larger here than it is in the mesial plane. The posterior lobe is small, and its neck, which is a very thin one, is not seen. The cleft is still seen, but the epithelium covering the posterior lobe is small in amount and is confined to that part of it which borders the cleft.


Herring1908b fig07.jpg

Fig. 7. Sagittal section through same pituitary as shown in fig. 6, but further to one side. Drawing from a photograph. b, tongue-like process of epithelium spreading forward: b’, epithelial cells spreading backwards over surface of the brain ; c, third ventricle ; d, anterior lobe ; g, epithelial cleft; h, posterior lobe; p, lymph space.


In the human embryo at this stage the intermediate part of the pituitary covering the neck and part of the posterior lobe is relatively smaller than it is in the cat embryo. But the intermediate part is not really reduced; it has changed its position, and in the human embryo is found to extend further over the surface of the brain. A thin layer (fig. 7, b) is prolonged forwards and backwards (b’) over the brain substance adjacent to the neck. The cells are arranged in columns, which may be a single cell thick, no lumen being found in them. Blood-vessels accompany this layer, and pass freely inwards into the brain substance, often carrying with them cells of the pars intermedia for a short distance along their course. The intimate relation of the cells of the pars intermedia to pars nervosa, and their differences in structure from the cells of the anterior lobe proper, appear to indicate that they are physiologically as well as anatomically connected with the brain. In the cat they are aggregated around the neck and body of the posterior lobe, which are hollow and in communication with the third ventricle. In animals which have a solid posterior lobe they are disposed more in relation to the brain substance adjacent to the neck, and in the monkey may spread inwards almost to the floor of the third ventricle.


In experiments which have been made on the physiological action of extracts of the posterior lobe, the material has usually been taken from the pituitary of the ox, on account of its size. An illustration (fig. 8) is given of the developing pituitary of the ox. In this animal the posterior lobe is a thin, solid, elongated structure. The epithelium of the intermediate part spreads widely over its anterior surface, as seen in the figure, but embraces it laterally as well, and passes for considerable distances in the form of columns of cells into the substance of the body of the lobe. Its epithelium is therefore closely bound up with the nervous substance of the lobe during development, and forms an important element in its composition. The question of the derivation of the active physiological principle of extracts of the posterior lobe has been discussed in a previous paper, and reasons have been given for regarding it as in great part derived from the epithelium of the pars intermedia. It is of interest, therefore, to find that in the development of the pituitary of the ox epithelial cells pass freely into the substance of the posterior lobe.


The disposition of the cells of the pars intermedia is such as to bring them into close relation with the neural canal in the region of the third ventricle. This of course follows from the history of the mode of development of the pituitary, but the spreading of epithelium over the surface and into the brain itself seems to indicate some further connection between the two. In fishes, e.g. the cod, the epithelium of the anterior lobe appears to have the same intimate connection with the nervous tissue of the posterior lobe which obtains in mammals and birds. The posterior lobe is hollow and has connected with it a large saccus vasculosus lined with folds of columnar epithelium. The saccus vasculosus is said by all who have worked at its development to be derived from the brain, and its secretion, if it is a secretory structure, passes into the third ventricle through the infundibulum. For this reason Rabl-Riickhard (25) called it an infundibular gland. No such structure is found in mammals, but Retzius (30) has described in them a slight swelling in the form of a clover leaf appearing on the surface of the brain behind the infundibulum, which he called the eminentia saccularis, and believed to be the homologue of the saccus vasculosus of fishes. Retzius described its external appearance only. In section, it is found to be a thinning of brain substance in the floor of the third ventricle in front of the corpora mamillaria. It is doubtful if this eminence is really homologous with the saccus vasculosus of fishes; it is not in the position one would expect, and should be sought rather in the postero-superior angle of the posterior lobe of the pituitary, where the blood-vessels enter, and where there is frequently in the cat, during development, the vascular knob already mentioned.


Fig. 8. Mesial sagittal section through developing pituitary body of ox. Drawing from a photograph. a, tongue-like process of epithelium spreading forwards; b, third ventricle; c, anterior lobe; d, e ithelial cleft; e, epithelium of para intermedia ; f, posterior lobe; 9, large lymph space extending into bo y of unifying sphenoid bone.


Although the mammalian brain has no saccus vasculosus, the posterior lobe of the pituitary possesses an investment of epithelium which differs from that of the anterior lobe, and it is because of the occurrence of colloid vesicles in this situation that the mammalian posterior lobe has been termed by Kiilliker (17) an infundibular gland. Whether the epithelium of the pars intermedia of the mammalian pituitary has a similar function to that of the saccus vasculosus of fishes is a difficult question to answer. Extracts of the saccus vasculosus of the cod do not appear to have the same physiological action as extracts of the posterior lobe of the mammalian pituitary when injected into the blood; but my investigations into the comparative physiology of the vertebrate pituitary are not sufficiently advanced to make any conclusivb statement on this point. The presence of epithelial cells of the pars intermedia in the interior of the cavity of the posterior lobe of the cat’s pituitary renders it probable that they furnish some material which passes in the direction of the brain. There must be some significance in the fact that in all craniate vertebrates the cerebrospinal canal has in close proximity to its anterior end, and intimately bound up with it, a glandular organ connected with the mouth. In the Ascidian larva a subneural gland or hypophysis cerebri occupies the same position. Andriezen (1) described in the Ammocoete and larval Amphioxus a subneural gland, a duct lined with ciliated epithelium affording a communication between the buccal and the neural cavities, and a group of nerve cells around and at the back of the upper opening where the duct Widens into the ventricular cavity; an arrangement, in fact, which is very similar to that found in the larval Ascidian. Andriezen believed that the buccal ventricular duct serves as an inlet for oxygenated water to the spinal cord, the nerve cells acting as a sensory mechanism to test the quality of the water admitted. In higher animals the water Vascular duct disappears and the-posterior lobe gradually loses its nerve substance. The anterior lobe or subneural gland alone remains functional, but its secretion is carried to the brain by lymphatics and blood-vessels. Sensory structures have been described in the infundibular region by Boeke (6) and by Gemelli (11) in fishes. There are, as already stated, no appearances indicative of such in the posterior lobe of mammals. Andriezen’s view is to some extent similar to the one expressed by Kupffer, but his anatomical data do not agree with the description of the larval Amphioxus as worked out by Willey and other authorities.


If the anterior lobe of the pituitary body is to be regarded as the remnant of an old mouth into the neural canal, it is possible that such a connection will occasionally show itself in the course of development. In one cat embryo I have met with a communication between the epithelial cleft and the central cavity of the posterior lobe. The opening between the two is at the postero-superior extremity of the posterior lobe, and it has been rendered possible by the spreading of Rathke’s sac further backwards than usual. The cleft or remnant of the original lumen of the buccal invagination is in open continuity through the infundibulum with the cavity of the third ventricle. The opening is a median one, and consists of a narrow canal lined by ependyma cells passing backwards from the wider lumen of the cavity of the body of the posterior lobe to meet with the fold of buccal mucous membrane and pass through it into its cleft. The ependyma cells cease where the canal meets epithelium, and the lining of its actual opening into the cleft is formed by the epithelium of the buccal invagination. The opening takes place at a comparatively late stage in development, after the buccal invagination has become separated from its origin by the growth of the sphenoid bone. I have examined many cat embryos, but have not met with another specimen showing actual con- tinuity of both cavities, although it is not unusual to find the appearances shown in figs. 10 and 11, where a somewhat similar condition exists; a canal runs backwards from the central cavity of the posterior lobe to meet the epithelium formed from the buccal invagination. In some kittens there is an indication of a tubular character of the epithelium of the pars intermedia in this situation, and the central cavity of the posterior lobe appears to run into it. In older animals epithelial cells often invade the tissue of the posterior lobe in the position in which the canal is indicated in the figures, and may come to lie in the central cavity. In one adult cat the nervous tissue of the posterior lobe is almost entirely destroyed by an overgrowth of epithelial cells of the pars intermedia. These observa- tions and the occurrence of epithelial cells in the brain substance of the floor of the third ventricle in the adult monkey seem to point to some physiological connection between epithelial cells and cerebro-spinal canal.



Fig. 9. Mesial sagittal section through postero-superior angle of the posterior lobe of the pituitary of a kitten near full time. Drawing from a photograph. a, part of epithelial cleft; b, central cavity of posterior lobe; c, nervous substance of posterior lobe ; d, canal from cavity of posterior lobe opening into cleft.


Fig. 10. Mesial sagittsl section through postero-superior angle of the posterior lobe of the pituitary of another kitten near full time. Drawing from a photograph. b, central cavity of posterior lobe; a substance of posterior lobe; d, canal from cavity of posterior lobe running backwards into 9, epithelial cells of the pars intermedin: f, cells of pairs intermedia investing posterior lobe below.


Fig. 11. Mesial sagittal section through postero-superior angle of the posterior lobe of the pituitary of a third kitten near full time. Drawing from a photograph. b, central cavity of posterior lobe; d. canal leading from this cavity into e, epithelial cells 1;: pa]!-ebientermedia ; f, cells of par: intermedio and cleft lying below the posterior lobe.


Since the intimate relations that exist between the two from the earliest stages of development are not only maintained but emphasised in the adult mammalian pituitary, it is unlikely that they are accidental, and Kupffer’s hypothesis as to the significance of the pituitary body appears to have many facts that support it. The nature of the connection between epithelium and cerebro-spinal canal from a physiological point of view awaits an explanation. It is possible that the epithelial cells secrete some substance which is necessary for the brain. Andriezen’s view that the secretion of the cells of the anterior lobe of the pituitary is carried by lymphatics and blood—vessels to the brain is unlikely, owing to the vascular arrangements in the lobe ; but it is probable that something of the kind occurs with the secretion of the cells of the pars intermedia. B. Haller regards the anterior lobe as a tubular gland which provides a secretion for the membranes of the brain and spinal cord. It is remarkable that there should be so large a cleft in the pituitaries of the dog and cat, unless it has some function. An external opening of the cleft is frequently seen, but it may quite Well be an artificial one, and in carefully prepared specimens I have been unable to find it. The anterior lobe is not a tubular gland, and the only cells that can pour a secretion into the cleft are those of the pars intermedia. On the other hand, the cleft is not always well developed even in the cat's pituitary, and may be almost entirely closed by fusion of the anterior lobe with the cells of the epithelial covering of the lobe. In the pituitary of the monkey there may be little remnant of the cleft, and certainly no opening from it into the subdural space. It is rare to find any histological evidence of a secretion into the cleft, and where colloid has been present it has been enclosed in a thin-walled cyst and not lying free in the cleft. In the rabbit’s pituitary it is not uncommon to find the cleft filled with red bone-marrow and fat cells. Lymph spaces in the dura mater below the pituitary body are frequently seen, but there is no evidence that they are specially connected with it: they probably belong to a system of lymphatics present at the base of the brain.

Conclusions and Summary

Development of the pituitary body begins very early in embryonic life. In mammals the epithelial portion is derived entirely from the ectodermic wall of the buccal invagination known as Rathke’s pouch. Its origin is single and mesial. The epithelium is differentiated at an early stage into two parts, which show differences in arrangement, structure, and vascularity. One of these, which has been termed the pars intermedia, is closely adherent to the Wall of the cerebral vesicle from its earliest appearance, and remains attached to it throughout life. It forms a layer of cells of varying thickness over body and neck of the posterior lobe and adjacent parts of the brain, and tends to arrange itself in positions where it can approach as near as possible to the cerebro-spinal canal. The cells of the pars intermedia are further characterised by the absence of deeply staining granules from their protoplasm, by their tendency to form a colloid substance in the adult organ, and by their comparatively poor supply of blood-vessels. Its relation to the nervous part of the pituitary and to the adjacent Wall of the brain tends to become even more intimate as development proceeds, by the ingrowth of its cells into these structures.


The other portion of buccal epithelium gives rise to the anterior lobe proper. The lower portion of Rathke’s pouch, which is not adherent to the brain, forms a solid mass of cells which grow into surrounding bloodchannels and into the cavity of the pouch itself. Its cells become filled with deeply staining granules and form columns without any lumen, separated from one another by blood-channels of a sinusoidal character. The original cavity of Rathke’s pouch persists as a narrow cleft separating the anterior lobe proper from the epithelial investment of the posterior lobe. The cleft remains a closed cavity, which varies in extent in different species and in different individuals of the same species. In the cat embryo there is evidence of some proliferation of cells of the anterior end of the fore-gut; these soon disappear, and do not enter into the formation of the adult pituitary.


The infundibulum is an invagination of part of the wall of the thalamencephalon which is adherent to the anterior and upper wall of Rathke’s pouch. It therefore possesses an epithelial covering derived from the latter. The infundibular process grows backwards, and, in the cat, retains its central cavity. It is lined by ependyma cells which during development become elongated, so that ependyma fibres run obliquely in its neck. The body of the lobe consists of ependyma and neuroglia cells and fibres; no true nerve cells are present in it, and there is very little connective tissue. The posterior lobe of the pituitary is, from the first, a composite structure of epithelium of the pars intermedia and of neuroglia and ependyma, and the relations between the two tissues become more and more intimate. Its vascular supply is derived from a different source from that of the anterior lobe; blood-vessels grow into it at its posterior-superior angle and form true capillaries in the lobe.


The intimate nature of the connection between the wall of Rathke’s pouch and the cerebral vesicle, and the maintenance of a close relationship between the cells of the pars intermedia and the cerebro-spinal canal, render it probable that the pituitary body of mammalia is to be regarded as the representative of an old mouth opening into the canal of the central nervous system. Such an arrangement exists in its simplest form in the Ascidian larva. A connection between Rathke’s pouch or original mouthcavity and the interior of the infundibulum is sometimes seen in the developing cat, and in the adult eat it is not uncommon to find epithelial cells, derived from the buccal cavity, lying inside the posterior lobe in communication with the third ventricle of the brain. The relations between epithelium and nervous tissue are not accidental in the mammalian pituitary. The latter may have arisen, as Willey stated, from a functional neuropore, but is more likelyto have been produced in the manner indicated by Kupffer. There is less probability of Dohrn'_s view being a correct solution of the problem. The question is one of great interest, and is by no means settled. The anterior lobe proper is a gland whose secretion must enter the blood directly, and so pass into the general circulation. The pars intermedia, on the other hand, appears to secrete into the brain tissue, and must be regarded as a brain gland. The nature of these secretions, and the question as to whether that of the pars intermedia is modified by its passage through brain substance, await further investigation.


I have to express my indebtedness to Mr Richard Muir for the care with which he has executed the accompanying illustrations. The expenses of the research have been defrayed by a grant from the Earl of Moray fund for the prosecution of research in the University of Edinburgh.

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