/. Embryo/, exp. Morph. Vol. 25, 2, pp. 247-261, 1971
247
Printed in Great Britain
Exocrine glands and the Chievitz organ
of some mouse mutants
By HANS GRUNEBERG 1
From University College London
SUMMARY
Thirteen mutant genes of the mouse have been scanned for the occurrence of anomalies of
glands of the head region and of the Chievitz organ. In eight of these (ic/ic; my/my; Ph/Ph;
Xt/Xt; Cd/Cd;fi/fi; or/or and ch/ch) such anomalies have been discovered; most of them are
absence or reduction in size of a gland, but increases in size or numbers have also been seen.
The anomalies are mainly and possibly entirely local consequences of pre-existing abnormalities of other organs and thus different from the systemic effect of the tabby syndrome.
But in at least one instance no local cause for an isolated glandular defect has been discovered.
INTRODUCTION
With the exception of the mammary glands, which have been studied because
of their relation to breast cancer, the exocrine glands of the mouse have received
scant attention. Only a few genetically determined anomalies have been described, such as the absence of the tarsal (Meibomian) glands in the mutant
crinkled (Falconer, Fraser & King, 1951), the absence of the exorbital lacrimal
gland in fidget (Truslove, 1956) and the absence of sebaceous glands in asebia
(Gates & Karasek, 1965). More recently, a syndrome involving a multitude of
glands and other structures of epithelial origin has been identified in tabby
(Griineberg, 1971); the tabby syndrome also occurs in some mimic genes
such as crinkled, and the absence of the Meibomian glands just referred to
is apart of it. As glandular anomalies often do not give rise to striking clinical
signs, they tend to be overlooked: the tabby syndrome has been with us for some
twenty years almost completely unnoticed, and the suspicion arises that this may
not have been a unique case. It thus became necessary to follow up some of the
hints afforded by these mutants in the hope that they might lead to the discovery
of additional glandular anomalies. These, in turn, might help to explain the
mechanisms which, in normal development, initiate the establishment of a highly
complex and orderly pattern of glands from a seemingly uniform surface epithelium. The results of this search will be presented in this paper. We have included
in this investigation the mysterious Chievitz organ, a ductless epithelial structure
of the cheek region: it turned out to be mildly affected by some and more
severely by others of the mutants which have been studied.
1
Author's address: Department of Animal Genetics, University College London, Wolfson
House, 4 Stephenson Way, London, NW1 2HE.
248
H. GRUNEBERG
MATERIAL AND METHODS
The search for possible glandular effects of mutant genes has been based on
hints provided by the systemic effects of the tabby syndrome (Griineberg, 1966,
1969, 1971) and by the local effects of fidget (Truslove, 1956). The tabby syndrome includes anomalies of the coat, the skin, the teeth and many glands; all
anomalies involve the downgrowth of a surface epithelium into the mesenchyme. There is a suspicion that something at the interface between epithelium
and mesenchyme may be at the bottom of it all. These facts and conjectures,
along with availability in the laboratory, led to the selection of the following
thirteen mutant genes. Five were included because they affect coat or skin
systemically:
(1) Ichthyosis (icjic; Carter & Phillips, 1950).
(2) Wavy-coat {RewcjRew0; Searle, 1968).
(3) Velvet-coat (Fe/+ ; Maddux, 1964).
(4) Plucked (pk/pk; Dickie, 1965).
(5) Soft-coat (soc/soc; Dickie, 1968).
Nos. 2-5 have not yet been described except in short notes in the Mouse News
Letter. Wavy-coat is an allele of the well-known hair-waving gene for rex.
Three genes were included on account of anomalies of liquid distribution in
embryonic life which leads to subepidermal blebs or to oedema and thus might
conceivably interfere with the down-growth of surface epithelia:
(6) Blebs (my/my; Carter, 1956, 1959; see also Griineberg, 1952).
(7) Patch (PhlPh; Griineberg & Truslove, 1960).
(8) Extra-toes (Xt\Xt\ Johnson, 1967).
In addition to possible systemic effects, these three genes might also affect
certain glands on a local basis. The my I my and the XtjXt mice have ocular
abnormalities; PhjPh has a cleft face which splits the nose longitudinally and
also results in cleft palate, and the nasal capsule of Xt/Xt is very abnormal.
(9) Crooked (Cd/Cd; Morgan, 1954; Griineberg, 1965) was included because
the complicated syndrome shares with tabby an involvement of the teeth and
a naked tail; the eyes are also abnormal. The remaining four genes were included
for a possible involvement of orbital glands:
(10)
(11)
(12)
(13)
Fidget (/z//7; Truslove, 1956).
Ocular retardation (or[or; Truslove, 1962).
Microphthalmia {mi\mi\ Hertwig, 1942; Miiller, 1950).
Congenital hydrocephalus (ch/ch; Gruneberg, 1943, 1953).
In ch/ch, in addition to the orbital glands which might be involved on account
of the open eyelids, the anomalous shape of the nose might affect the nasal
glands.
The head region has a wide variety of glands and thus would certainly be
involved in any systemic disturbance; most of the glands can be identified in the
Exocrine glands of mouse mutants
249
newborn. In most instances, if the first specimen of a mutant showed no significant abnormalities, no more were examined. Inconstant gene effects are thus
liable to have been missed. Where the first mutant specimen proved abnormal,
additional individuals were examined along with some normal litter-mates to
distinguish effects of the mutant gene from those of the genetic background. But
generally three pairs of animals were regarded as sufficient if the situation was
reasonably well understood. In some instances (such as XtjXt and chjch, which
die at birth), late foetal material was preferable, and in some instances embryonic
material was also examined. All heads were sectioned serially in the transverse
(frontal) plane: embryos at 10 JLI, late foetuses (17-18 days) at 12^ /A, and newborn
or older individuals at 15/*; Bouin fixation and staining with H and E were
used. The material is set out in Table 1. In some instances additional dissections
were carried out by Mr A. J. Lee.
Table 1. The material studied histologically
Late foetuses
(17-15I days)
Mutant
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
Embryos
(pairs) Mutant
Newborn
and older
A
Normal
Mutant
Ichthyosis
4
1
Wavy-coat
1
Velvet-coat
1
Plucked
1
Soft-coat
3
Blebs
1
2
Patch
Extra-toes
3t
2
1
1
3
Crooked
2
Fidget
3
Ocular retardation
3
Microphthalmia
2
6
5
2
Cong, hydrocephalus
* Perhaps a my/my normal overlap; no glandular abnormalities.
t Full-term foetuses.
Normal
4
1*
3t
3
2
3
1
RESULTS
1. Glandular effects of mutant genes
For a description of the more important glands of the head region of the
mouse see Gruneberg (1971). The glands do not vary much in normal mice or
in the normal regions of mutant mice. Absence of major glands has not been
encountered nor do the glands vary much in size. A common minor variant is
the presence of an accessory gl.nasalis medialis, generally in the neighbourhood
of the gl.nas.med. I and III; it is usually unilateral only, but occasionally bilateral. On three occasions, one gl.nas.med. IV was absent. The number of ducts
of the gl.buccalis is not constant. No doubt other variations could be detected by
a more detailed study, but the overall picture is one of uniformity.
250
H. GRUNEBERG
In five out of the thirteen genes studied, no significant glandular anomalies
have been discovered. They are RewcjRewc, Vej + ,pk/pk, soc/soc and mi/mi. The
glandular anomalies of the other eight mutants are summarized in Table 2 along
with the effects of the tabby syndrome for comparison; + + + indicates complete
absence of the gland in all mutant animals examined, and + + absence of a
majority of the glands or a considerable reduction in size. A + sign indicates
lesser though probably significant involvement of a gland or one member of
a group of glands; it usually indicates a reduction, but in a few instances an
increase in size. A ' . ' means that no anomaly has been discovered. The eight
mutants with glandular anomalies will now be described in order of ascending
complexity of the situation; glands not specifically mentioned are normal or
nearly so.
Table 2. Glands of the head region and the Chievitz organ in the tabby
syndrome and in eight of the mutant genes studied
Ta*
Gl. submaxillaris
sublingualis major
parotis
parotis accessoria
sebacea anguli oris
buccalis
linguales laterales
linguales mediales (v. Ebner)
palatinae
glosso-palatina
nasalis lateralis 1 (Steno)
nasales laterales II et seq.
nasales mediales
nasales infraseptales
Bowman's glands
Gl. anterior organi Jakobsoni
propriae sinus maxillaris
mucosae tubae auditivae
nasopharyngeae
ceruminosa
tarsales (Meibom)
lacrimalis intraorbitalis
lacrimalis exorbitalis
Harderian gland
Chievitz organ
Cd/Cd
.
.
.
.
.
.
+
+ + ++
+++
++
+++
+++
.
++
++++
+++ .
.
.
.
.
.
+++
+++
++
+++
+++
+
++
.
ch/ch
Xt/Xt Ph/Ph my I my orIor
.
.
.
.
.
+
.
.
.
.
.
.
.
+++
+++
.
.
.
.
.
.
.
+
+
+
+
++
++
+ +
+
+
.
+
.
.
.
.
.
.
+++
++
+++
+++
+
+
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
+
.
.
.
.
.
.
?t
+
.
++
ic/ic
.
.
.
+
.
.
.
.
.
.
.
.
+
+
+
.
.
.
.
.
filfi
.
.
.
.
.
+ 4.
+ +
+ + + + + + +
++
.
.
.
+ +
* Based on Griineberg (1970), except for the Chievitz organ.
t Doubtful on account of immaturity of specimens available.
Blebs (my I my). In this mutant, subepidermal blebs are present from the 12-day
stage onwards, particularly on eyes and feet, but the overall hydration does not
differ significantly from that of normal embryos (Johnson, 1971). In two mutant
animals the right eyes and glands were normal; the left eyes were grossly abnormal; both lacked the Harderian and the exorbital lacrimal glands and one
Exocrine glands of mouse mutants
251
also the intraorbital lacrimal gland. The third animal had mildly abnormal eyes
on both sides; the left of them lacked the Harderian gland. The purely local
character of the glandular defects is obvious.
Fidget (filfi). In agreement with the findings of Truslove (1956), two 3-da.yfi/fi
mice lacked the exorbital lacrimal glands and one also the right intraorbital one.
As filfi embryos have reduced eyes from the 10-day stage onwards, the glandular
defects are adequately explained on a local basis.
Ocular retardation (orjor). One out of three newborn orjor mice lacked the
right exorbital lacrimal gland and another lacked both glands. Again, as eye
anomalies are present in the 11-day stage (i.e. well before these glands originate in
normal development), they are a sufficient explanation. Further defects of
orbital glands in chjch and XtjXt will be described below. However, eye defects
do not automatically involve the orbital glands. Those in crooked (Cd/Cd; see
below) are mostly normal, and no abnormalities have been discovered in microphthalmia (mi/mi; see above), although a striking coloboma is present from the
10-day stage onwards (Miiller, 1950). By way of contrast, the following case
shows that glandular defects may be present in the absence of obvious eye
defects.
Ichthyosis {icjic). Two pairs of 2-day and two pairs of 8-day mice were
examined. Two icjic mice lacked both Harderian glands and one the right-hand
one only (as usual, ghost glands were present); one 2-day individual had both
glands; as at that stage classification is difficult, the possibility cannot be ruled
out that that mouse was in fact normal. Graphical reconstructions from sections
carried out by Mr A. J. Lee failed to show abnormalities of the nictitating membrane or its vicinity, at least in the 8-day stage; nor were any discovered by
dissection of adults. A detailed examination of the conjunctiva has not yet been
carried out. Considering that icjic is evidently near a threshold beyond which
the formation of a normal gland is still possible, a major abnormality was
perhaps not to be expected.
Crooked (CdjCd). There is no obvious local explanation for two isolated
glandular anomalies which are characteristic for this mutant. The gl.nas.med.
IV tend to be absent. These glands arise in the 15-day embryo as hemispherical
buds; diffuse swellings only were present in the 15-day CdjCd embryo, which
apparently either regress or give rise to rudimentary glands. The latter was the
case in a 16-day CdjCd embryo (glands in three and six sections as compared
with seventeen and eighteen in the normal). The gland was completely absent
on the left in an 18-day CdjCd foetus and bilaterally in all three newborns
examined. As this gland is sometimes absent in otherwise normal mice, the
absence of a major abnormality to account for its involvement in CdjCd may
not be surprising. The second anomaly affects the gl.buccalis which arises, also
on day 15, in the cheek behind the lower second molar. This gland was absent
bilaterally except in the 16-day embryo, which had reduced ones (two and five
sections as compared with twelve and nine in the normal); no clearly identifiable
17
EMB 25
252
H. GRUNEBERG
buds were present in the 15-day embryo. Evidently, the situation is similar to
that in the gl.nas.med. IV. Slight anomalies of one lacrimal duct (18-day foetus)
and absence of one exorbital lacrimal gland (in a newborn) can be accounted
for on a local basis. No other glandular abnormalities were discovered in Cd/Cd.
Patch (Ph/Ph). The inviable homozygotes of this spotting gene are hydropic
and usually die about the 10-day stage; about one-third survive longer with
a cleft-face and cleft palate syndrome. The nose is completely cleft, with a large
bleb separating the two halves, each of which is surrounded by a separate
capsule; there is no nasal septum; many subepidermal blebs occur elsewhere.
I examined one pair of 15-day embryos and two PhjPh which, though retarded,
survived to be born - a rare event. Systemic and local effects on nose and palate
were expected. However, the nasal glands turned out to be surprisingly normal.
The lateral nasal glands (including Steno's gland) are normal or nearly so; on
the medial side of the separate nasal capsules three (rather than four) medial
nasal glands are present. In the 15-day embryo the gl.nas.infraseptalis posterior
is present, but the anterior one is not (? yet) present; one of the other animals
has two, the other one pair of infraseptal glands which turn medially on leaving
the nasal capsule, though of course they cannot occupy their normal position
in the absence of a septum. In the 15-day embryo there are no buds of the
gl.palatinae, presumably a sign of immaturity as compared with the normal
litter-mate, in which buds are already present. But in both older specimens these
glands are present in spite of the cleft palate. Whereas thus the expected local
effects were not found, some unexpected ones were present. The gl.parotis
accessoria is much larger than normal; this must be a real effect as all three
PhjPh individuals are considerably retarded. The main body of the gl.parotis is
reduced in size, as is the anterior region of the Chievitz organ (see below). These
anomalies may be a consequence of the changed proportions of the PhjPh head;
anomalously, the ductus parotideus originates from the buccal mucosa at
a level anterior to the orifices of the other large salivary glands under the tongue.
The absence of the left lacrimal duct with glands in one of the newborn PhjPh
mice may have been caused by a subepidermal bleb and is thus presumably
a local effect. The absence of some glands which arise near the time of birth is
presumably due to immaturity alone.
Extra-toes (Xt/Xt). The lethal XtjXt embryo has a marked general oedema
which is detectable from the 12-day stage onwards (Johnson, 1971) and which
thus might conceivably interfere systemically with glandular development.
Otherwise the complicated syndrome (Johnson, 1967) includes features which
might give rise to local glandular effects, a reduction of the eyes, absence of the
olfactory lobes of the brain and a striking narrowing of the nasal passages in the
vestibular region where most of the nasal glands originate. A litter of full-term
foetuses including three XtjXt, one Xt\ + and two + / + individuals has been
studied. In all three Xt\Xfs intraorbital and exorbital lacrimal glands are symmetrically absent, and in one of them both Harderian glands are also missing.
Exocrine glands of mouse mutants
253
To a varying extent, all three Xt/Xfs show a reduction of Bowman's glands;
this is presumably somehow related to absence of the olfactory lobes of the
brain with its consequences on the development of the olfactory epithelium.
The three XtjXfs form a graded series as regards the severity of the nasal abnormalities. In one of them the vestibular region is completely pinched through,
so that a cartilaginous barrier separates the region of the nostrils from the rest
of the nasal passages; these are very narrow, the maxilloturbinal is rudimentary
and lacks a cartilaginous core, and the nasolacrimal ducts fail to reach the nasal
passages. All the gl.nas.mediales and laterales are missing, as are the infraseptales
with the exception of one on the left which occupies a fairly normal position
under the septum. The organs of Jakobson are very small, but the glands associated with them are much larger than normal and spread up the septum into
positions normally occupied by the gl.nas.mediales. The two other individuals
are less extreme in that in one there is continuity of the nasal epithelium and in
the other even a narrow lumen. A few rudimentary nasal glands are present, including one Steno's gland in the least abnormal specimen. In both individuals
the glands of Jakobson's organ are hyperplastic and the gl.sinus maxillaris
propriae spread into a region of the maxillary sinus normally occupied by
Steno's gland. All glandular anomalies of XtjXt can thus be accounted for on
a local basis.
Congenital hydrocephalus {chjch). A systemic anomaly of the membranous
skeleton leads to hydrocephalus, which first appears at the 12^-day stage. The
eyelids remain open, perhaps because of lateral displacement of the eyeballs or
on account of abnormal tension on the surrounding skin. One striking though
fairly late effect of the gene has previously escaped notice. There is regularly
(17-day foetuses and later) an osseous fusion between maxilla and mandible; in
the most extreme cases the molars may also get involved; upper and lower ones,
instead of facing each other, may stand side by side in a common lateral crypt
and face the side of the tongue. The masseter is greatly reduced or absent, and
it may be surmised that immobility of the jaws leads to their ultimate fusion.
The glandular involvement of chjch is more complicated than that of the
other mutants. Three sites are affected. For two of these (absence of Harderian
glands, and absence of the parotis with reduction of the Chievitz organ), local
mechanisms are almost certainly responsible. Complicated changes in the nasal
glands are less well understood, but in the last analysis may also turn out to be
local in origin.
(1) Normally, the Harderian glands arise from the nictitating membrane in
14-day embryos. Those of chjch are regularly absent except for ghost glands.
Graphical reconstructions of 13^-day embryos (two normals, two chjch) made
by Mr A. J. Lee show that the relevant region is already somewhat deformed at
that stage and hence prior to the formation of the glands. There is thus prima
facie evidence for the local origin of this defect.
For unknown reasons, the eyes of the two newborn chjch mice were grossly
17-2
254
H. GRUNEBERG
abnormal in structure; one lacked both lacrimal ducts with the associated glands,
the other that on the right-hand side. The anomalies are clearly local in origin.
As all other chjch's seen now and in the past had normal eyes, it is uncertain
whether the eye defects of these animals had anything to do with ch, and these
glandular anomalies have not been included in Table 2.
(2) The parotis and accessory parotis of chjch is generally absent and the
Chievitz organ (see below) is greatly reduced anteriorly. Once only was a rudimentary but clearly identifiable ductus parotideus (11 sections) found on the
more normal left side of a 17-day foetus. There can be little doubt that these
defects and the reduction of the masseter with fusion between maxilla and
mandible have a common local cause, though the mutual relationships of the
defects are not yet clear.
(3) Some of the disparate anomalies of the nasal glands are constant, others
variable. Normally there are four pairs of gl.nas.mediales, I and III more dorsally, II and IV more ventrally on the nasal septum (see fig. 2 in Griineberg,
1971). A small accessory pair near glands I and III is regularly present in chjch;
less regularly, there is also an accessory gland which originates on the dorsal
wall of the nasal duct and then turns medially towards the septum (once bilaterally, four times unilaterally out of eight chjch examined). By contrast,
gland IV is often absent or rudimentary, as in CdjCd (see above). All three
variants occur sporadically in otherwise normal mice. Medial, lateral and infraseptal glands may form variable massive and often bizarre lumps of glandular
tissue; one variant is the invasion by glandular masses of the medial aspect of
the nasoturbinals, which is normally free of glands. All these dissimilar anomalies may have a common denominator. They arise in a mesenchyme which
is in direct contact with the abnormal nasal capsule and which gives the
impression of being more massive than normal. If this should be the reason, the
glandular anomalies of the nose, diverse though they are, would have to be
regarded as local phenomena.
The same may be true for an anomaly of Jakobson's organ which is regularly
present in ch/ch; an excess of material on the dorsal aspect of the organ leads to
a distortion of the lumen; the associated glands arise laterally instead of dorsally
as in the normal.
2. The Chievitz organ
This enigmatic epithelial organ was first described by Chievitz (1885), after
whom it is now usually named (reviews in Schumacher, 1927; Fahrenholz, 1937).
Other names ('ramus mandibularis ductus parotidei'; 'orbital inclusion';
' tractus bucco-pharyngeus'; ' organum bucco-temporale') indicate some of its
topographical relations. It has been found in the embryos of many mammals,
including man, and is probably a general mammalian feature. The Chievitz
organ has been regarded as a transitory embryonic organ though it has once
been identified in a human newborn. In the mouse, at any rate, it is regularly
Exocrine glands of mouse mutants
255
present at birth and beyond; its postnatal growth seems, however, to be limited:
in two fully adult animals (264 days) its cauda was only about twice as long as
at birth and the corpus if anything thinner. As, without a special search, this
small structure can easily be missed both by dissection and in sections, its
persistence into adult life may not be peculiar to the mouse.
The Chievitz organ (or c.o. for short) is a long, thin and solid strand of
epithelial tissue which is about circular in cross-section. Three regions (cervix,
corpus and cauda; Fig. 1) can be distinguished. The corpus is situated on the
Bud of Gl. lacrimalis
intraorbitalis
Parotis accessoria
Gl. lacrimalis exorbitalis
Chievitz organ
(cauda)
2 mm
2 mm
B
Fig. 1. (A) Dissection of head of normal newborn mouse. (B) Graphical reconstruction from serial sections of the Chievitz organ (black) in relation to skull basis and
pterygoid muscles; ventral view. 1, corpus of Chievitz organ; 2, cervix of c.o.; 3,
processus zygomaticus ossis maxillaris; 4, m.temporalis; 5, m.masseter, posterior
superficial portion; 6, idem, anterior superficial portion; 7, m.pterygoideus externus;
8, m.pterygoideus internus; 9, os maxillare; 10, os palatinum; 1.1, os pterygoideum.
* indicates the point where the c.o. bends round the anterior margin of the masseter,
and ** where it bends round the anterior margin of the temporalis.
medial surface of the m.masseter; on reaching the anterior superficial masseter
tendon it turns sharply backwards and thus comes to lie on the lateral surface
of the masseter; this part of the organ, here referred to as the cauda, usually
forms a gradually tapering strand which is firmly attached to the muscle and
indeed often occupies a shallow groove in it; sometimes its free end fails to
attach itself to the muscle and then tends to be bulbous. As the cauda is sharply
defined by the angle where it turns round the tendon and its free end, it lends
itself to measurement (by counting sections). At the other end, the corpus
continues dorsally and posteriorly and loops medially round the inner portion
of the m.temporalis; from here onwards it may be called the cervix, which ends
(usually club-shaped) lateral to the pterygoid and a little behind the level of the
papilla vallata of the tongue. In view of its complicated topography, Figs. 2
256
H. GRUNEBERG
and 3 are given to aid in the identification of the c.o. and Fig. 4 shows its histological appearance.
The c.o. develops adjacent to the gl.parotis but, at least in the mouse, they
are completely separate from each other. The parotis originates as a well-defined
Eye
cut tangentially)
Temporalis
Zygomatic arch
Palate
Posterior superficial masseter
Parotid duct
Anterior superficial masseter
Chievitz organ
Mandible
Incisor
Fig. 2. Topographical relations of the anterior part of the corpus and of the cauda
of the Chievitz organ. The area enclosed by the rectangle is shown at higher
magnification in Fig. 4.
Mandibular
articulation
Nasopharynx
Pterygoideum
/
V ganglion
.'.'.'
Pterygoideus
externus
Meckel's
cartilage
Pterygoideus
internus
Masseter
Fig. 3. Topographical relations of the cervix of the Chievitz organ (arrows)
near its posterior end.
Exocrine glands of mouse mutants
257
bud a little behind the primitive angulus oris from the sharp angle of the buccal
cavity in the 12^-day embryo. The c.o. arises a little earlier (12-day stage) from
the same buccal angle somewhat posterior to the ductus parotideus, but in the
form of a flange; this remains accurately aligned to that angle after it has separated from it. By contrast, cervix and cauda seem to grow out from the two
ends of the corpus and come to lie far from the region of origin of the c.o.
As the c.o. is a ductless epithelial structure, it has been suggested that it
might be an endocrine gland. This is not implausible, but proof by surgical
removal of both Chievitz organs would present formidable difficulties. Hence
the question of whether the c.o. has a function is still open.
Fig. 4. Chievitz organ of a 2-day-old normal mouse from the ichthyosis stock. Left,
the area indicated in Fig. 2 (x 100); right, the cauda of the c.o. (x 415).
Some quantitative data for the cauda of the c.o. are given in Table 3; Ph/Ph
and chjch are omitted as their c.O. is very abnormal and does not include a cauda
at all (see below). The cauda ofXt/Xt. is reduced in length; the only Xtj + mouse
examined is like a normal in this respect; the difference is due to absence of the
tapering end of the cauda. The same is true for CdjCd; here, the only Cd/ +
mouse examined falls into the CdjCd range. The other six mutants appear to be
normal. But there are some inter-strain differences which are presumably
genetic; for instance, in the or-stock (which is genetically heterogeneous) mutants
and normals alike have short caudae. Though clearly significant, the differences
in Table 3 are of a minor kind, and similar differentials might have come to
light in the glands if these had been measured.
258
H. GRUNEBERG
Table 3. Chievitz organ: length (/*) of right and left cauda combined. (For comparison, the caudae of two 264-days-old mice measured 2280 and 2440 ju respectively.
Nb = newborn.)
Mutant
Age
(days)
XtIXt
Cd/Cd
Ta
A
Nb
15
16
18
Nb
14
15
16
1305
1090
1160
1330
1410
630
760
980
Nb
900
my/my
Nb
720 %
or/or
mi/mi
ic/ic
Nb
Nb
2d
3d
filfi
*
f
J
§
Mutant
Normal
240
1425
450
1260
1260
315
520
410
680
0
450
750
1200
930
1350
450
255
2115
1605
615
480
1170*
345
525
315f
390
240
555
405
1725
1530
1275
405
1425
1800
1020
330
525§
Xtl + heterozygote.
Cdj + heterozygote; right cauda only (left one absent).
Perhaps a my/my normal overlap.
Left organ only; right one anomalous and not measurable.
Parotis accessoria
Buccal
cavity
Normal
Patch
Patch
Fig. 5. Graphical reconstructions from serial sections (dorsal view) of the right
ductus parotidis, parotis accessoria and Chievitz organ in a normal newborn
mouse (A) and in two newborn Ph/Ph individuals (B, C).
Exocrine glands of mouse mutants
259
By contrast, both Ph/Ph and chjch affect the c.o. severely, and in either case
the parotis is also involved; it thus seems that both organs are affected by
a common local disturbance. In PhjPh (Fig. 5) the corpus is coarse and irregular
in outline; it may not extend as far forward as the masseter tendon and the
cauda is absent. The associated anomalies of the gl.parotis accessoria have
already been mentioned. In ch/ch the parotis and parotis accessoria are completely missing; the c.o. is sometimes only represented by somewhat dubious
epithelial structures far backwards; usually the cervix and posterior part of the
corpus can be identified, but the anterior part of the c.o. is not present at all.
Evidently, there is a local disturbance which interferes both with the formation
of the parotis and of the anterior region of the c.o.
DISCUSSION
The glandular anomalies of the tabby syndrome are widely distributed over
the body and local causes are not demonstrable. Moreover, the effects are
co-ordinated and due to a mechanism which the glands share with other derivatives of the surface epithelium. The situation is quite different in at least four
of the eight mutants with glandular anomalies described in this paper (my/my;
fijfi; or I or and XtjXt). In each case the glandular defects are strictly localized at
sites of pre-existing deformities and, being thus adequately accounted for as
secondary to other gene effects, they can be dismissed from further consideration. This also applies to glands which are increased in size because they have
spread into territory normally occupied by other glands (such as those of
Jakobson's organ in XtfXt). Presumably the localized effects of patch on parotis
and the Chievitz organ trace back to the altered head shape of Ph/Ph embryos
as shown by the interchanged levels of origin of the major salivary glands from
the oral mucosa.
Whereas the glandular effects of four and probably five mutant genes can
thus be dismissed as local and secondary, the situation is less clear for the three
other mutants. In ichthyosis (icjic) absence of Harderian glands is local, but
without obvious local cause. The same is true for the two glandular defects of
crooked (CdjCd), i.e. absence or reduction of the gl.nas.med. IV and of the
gl.buccalis. As there is no evidence for a systemic glandular effect, one is driven
to invoke local mechanisms which are not detectable (or, at any rate, which have
not been detected) microscopically. The anomaly of the gl.buccalis in CdjCd
may somehow be related to the reduction of the second and third lower molars
(Griineberg, 1965) in whose vicinity the gland arises; and as the gl.nas.med. IV
is sometimes absent in otherwise normal mice, it seems to be a structure which
can be pushed over the brink by rather minor events. Finally, in chjch, absence
of the Harderian glands and the anomalies of the parotis and the Chievitz organ
are probably of local origin, and the same may well be true of the anomalies of
the nasal glands. It seems, then, that there is good evidence for the local origin
260
H. GRUNEBERG
of many of the glandular defects here described, and the rest can be so interpreted without forcing the facts. On the other hand, there is no evidence that
any of the mutants affects the glandular system as such, and in particular my I my,
Xt\Xt and Ph\Ph have shown no signs of a systemic effect. Evidently, the
glandular anomalies of the tabby syndrome are quite different from the local
ones described in this paper.
The local glandular effects form a continuous scale from obvious consequences
of gross structural deformities, through anomalies which are only occasionally
associated with disturbances of local glands (like the eye defects of Cd\Cd) down
to massive defects which, like Ph/Ph (as regards nose and palate), affect the
local glands little or, like mi/mi, apparently not at all. Finally, there are instances
(like icjic) where a local cause of a local effect is postulated rather than observed.
The top end of the scale has little to offer for the understanding of gene effects
or the factors which lead to normal glandular development. But as one passes
down the scale things become more promising, and if cases like the simultaneous
existence of glandular defects and excess formations (in the nose of chjch) can
be brought nearer understanding, real progress may be made.
Early studies of developmental genetics in mammals were hampered by
paucity of material. Mutant genes had to be studied as they became available
and similar conditions could rarely be compared with each other. A weakness of
this type of study was that it was difficult to get independent verification concerning causalities thus inferred. To use a comparison, the situation was like
trying to solve a crossword puzzle by means of the 'downwards' clues alone;
this may give plausible answers but they will not necessarily be the correct ones.
By using the 'across' clues as well, the number of answers satisfying both is
greatly reduced. The present paper falls into the latter category.
I am greatly indebted to Miss Beryl F. Fannon for devoted technical assistance and to
Mr A. J. Lee for the illustrations and help in various ways. Drs. M. S. Deol, D. R. Johnson
and Gillian M. Truslove kindly allowed me to use some of their sectioned material.
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(Manuscript received 5 November 1970)