J. Embryol. exp. Morph., Vol. 14, Part 2, pp. 137-159, October 1965
Printed in Great Britain
Genes and genotypes affecting the teeth of
the mouse
by HANS GRUNEBERG1
from the M.R.C. Experimental Genetics Research Unit, University College, London
This paper is dedicated in gratitude and affection to Professor Hans Nachtsheim
on the occasion of his seventy-fifth birthday (13th June 1965).
T H E teeth of mammals have been studied in great detail both by palaeontologists
and by taxonomists who are interested in differences between species or higher
systematic categories which are ultimately genetic in nature. By contrast, little is
known about intra-specific genetic variability of the dentition. An invitation to
participate in an 'Institute for Advanced Education in Dental Research'
sponsored by the American College of Dentists provided an occasion to explore
the situation in the laboratory and, presently, in the wild house mouse. The main
results of this search are given in this paper. The extent of the intra-specific
variance discovered may help systematists in assessing how much importance
to attach to the differences they encounter; and it will be shown how easily one
can be misled, in a limited sample, as to what is 'normal'. Two characteristic
dental syndromes to be described pose a new kind of problem to dental pathology.
The fact that their interpretation in developmental terms is far from obvious may
act as a stimulus to further work on the embryology of both the dental crown and
the roots. The material to be described in this paper offers opportunities for
such an approach not hitherto available.
OBSERVATIONS
Terminology
In referring to the various molars, we shall use the symbols m l5 m2 and m 3 for
the lower and similarly m1 , m 2 and m 3 for the upper ones. The surfaces will be
referred to as buccal and lingual, as anterior and posterior, and as occlusal and
basal respectively. As in this paper we are concerned with the teeth of a single
species, we can avoid the difficult terminology used by palaeontologists to
homologize cusps in different organisms. Following Gaunt (1955), the cusps
are numbered (Text-fig. 1). For instance, in m 1 and m2 which have three rows of
1
Author's address: Medical Research Council Experimental Genetics Research Unit,
University College, Gower Street, London, W.C.I, U.K.
138
H. GRUNEBERG
cusps, the main (central) row is numbered from front to back as 1, 2 and 3
respectively in m 1 and 2 and 3 respectively in m 2 ; the buccal cusps are labelled
Bl, B2 and B3, and the lingual cusps LI and L2 respectively.
The lower molars have only two rows of cusps (LI, L2 and L3, and Bl, B2 and
B3 in m1} of which LI occupies the anterior position of the tooth), except that
MAXILLARY
MAND1BULAR
LI
L2
L3
J
4
L2 L3
BUCCAL
LINGUAL
POSTERIOR
BUCCAL
B3 B2
Bl
B3 B2
Bl
4,
LINGUAL
POSTERIOR
1. Outline drawings of the left molars of a 60-days-old normal mouse female. The
arrows in this drawing, as in all others, point forward. The posterior aspect shown for m3 and
m3 is normal to the axis of the tooth; the axis of both slopes anteriorly in situ. All drawings
in this paper are camera lucida drawings made by Mr A. J. Lee.
TEXT-FIG.
there is a smaller cusp (designated as 4) which occupies the posterior end of both
mj and m 2 and thus belongs neither to the buccal nor the lingual row of cusps.
In one respect, Text-fig. 1 differs from Gaunt's descriptions. According to
Gaunt, m 2 lacks the cusp Bl. In all normal mice examined by the present author,
such a cusp was present; it is separated from the larger cusp B2 by a sulcus and
often has a separate tip which stands out in profile (see, e.g., Text-figs. 1,11 and
16). Gaunt used for his studies an (unspecified) inbred strain which differed in
this respect (as also in the close proximity of Bl and B2 of m{) from the normal
pattern. Whereas Bl of m 2 was regularly present in normal mice, the cusp
disappears completely in the mutants Ta and cr which will be described below.
Genetics of the dentition in the mouse
139
Minor dental variations
The alleged phenotypical uniformity of genetically heterogeneous populations
is a myth. Structural variations, not all of them 'minor', can be discovered in any
organ which is adequately studied, and the teeth are no exception. For practical
purposes it is more useful to compare a number of inbred strains as a variant
once located can easily be found again if subsequently required for further studies.
The present study is mainly based, so far as the minor variants are concerned, on
the strains CBA, C57BL, A and BALB/c for which ample material was available
in our collections. As will be described presently, many characteristic differences
CBA
C57BL
BALB/c
2 mm.
TEXT-FIG.
2. Buccal views of left m1 from four inbred strains (CBA ?, 61 days old; C57BL $,
65 days old; BALB/c $, 59 days old; and A ?, 31 days old).
have been discovered, and others would no doubt have come to light if more
inbred strains had been included in the survey. Within each strain, dental
morphology proved to be remarkably constant so that comparison of ten
individuals from each strain was quite sufficient to establish the inter-strain
differences.
Variations in m 1 (Text-figs. 2 and 3) include the presence of an extra cusp in
strain A which is interposed between cusps B2 and B3; it was present in all
twenty teeth of the A strain examined, but absent from the corresponding sixty
teeth of the other three strains. In strain BALB/c, the same two cusps are connected by a flat ridge or curtain; again, this was present in all twenty BALB/c
teeth, but not in any from strains CBA or C57BL. Less conspicuous is a ridge
140
H. GRUNEBERG
which, in CBA, leads from the posterior margin of cusp B2 in a lingual and
posterior direction towards the central cusp 3; a somewhat similar ridge and
roughly parallel to it is also present along the posterior margin of cusp B1. Again,
this configuration is typical of CBA. Other differences are found in cusp B3; that
cusp merges smoothly into the central cusp 3 posteriorly, except in C57BL where
it is separated from 3 by a distinct notch; indeed, the separation of B3 from 3 is
sometimes even more marked (see, e.g., Text-fig. 4, b). Other differences will be
noticed by careful comparison.
C57BL
CBA
BALB/c
2 mm.
TEXT-FIG.
3. Crown views of m1 in four inbred strains. Same teeth as in Text-fig. 2.
In all four inbred strains, as indeed in virtually all normal mice examined, the
central cusp 1 as seen in profile curves smoothly down to the neck of the tooth
where the anterior buccal root originates. Gaunt's (1955) drawings show the
same configuration which must clearly be regarded as normal. It was therefore
somewhat disconcerting to discover that the 'normal' m 1 which I had used for
comparison with a grey-lethal tooth (Griineberg, 1937, Text-figs. 3 and 4, p. 238)
had a distinct extra cusp near the base of cusp 1. The cusp in question was in
fact present in several 'normal' mice of the grey-lethal stock at that time. What
has happened to the extra cusp in the meantime ? A survey of mice from many
different stocks in our collections disclosed the presence of a similar cusp in a
mutant stock segregating for the gene for pudgy (pu); it was present both in
normal and in mutant mice; pu had originated in the' specific locus' experiments
in Oak Ridge, Tennessee, U.S.A. Two inbred strains, C3H and 101, contribute
to that experiment, along with a strain carrying 7 recessive genes; two skeletons
each of these three strains were obtained from the Radiobiological Research
Unit, Harwell, Berks. All four m 1 of the 101 strain clearly showed the extra cusp
Genetics of the dentition in the mouse
141
(Text-fig. 4, a), and that strain almost certainly is the source of the cusp in the
pudgy stock; but a rudimentary cusp in about the same position was also present
in one of the four C3H teeth. The 101 differs from the 1937 cusp in that it is
slightly displaced from the middle and thus more conspicuous from the lingual
than from the buccal aspect. However, a cusp more nearly like the 1937 one was
discovered in a heterogeneous strain segregating for shaker with syndactylism
(sy); it has nothing to do with that gene (Text-fig. 4, b). Moreover, a similar cusp
was found in six out of twenty-four wild house mice caught in 1959 in various
grain shops in Delhi (Gruneberg, unpubl.); the expressivity varied somewhat,
4. Buccal and crown views of left m1 with extra cusps near the base of cusp 1.
a, 101 strain £ from Harwell, 52 days old. b, mouse homozygous for shaker with syndactylism, 24 days old (which lived in 1950).
TEXT-FIG.
but five out of the six mice showed the cusp symmetrically. Whereas the genetical
nature of these various cusps is beyond doubt, only that in strain 101 is readily
available for further study. It is of interest to note that a similar cuspule of m 1
is a normal feature in the golden hamster, Mesocricetus auratus (Gaunt, 1961).
The extra cusp just mentioned in wild house mice from India is not the only
dental variant found in that sample. Dental variants were also found in a
similar sample from a rick on a farm in Hampshire (collected by my colleague,
Dr R. J. Berry). The occurrence of these characteristic dental variants in
populations of wild mice is here emphasized for the benefit of palaeontologists
and taxonomists who might otherwise be inclined to disregard the findings of
this paper as a peculiarity of laboratory animals.
Turning to m l5 there are again striking differences between the four inbred
strains (Text-figs. 5 and 6). In CBA and A, cusp LI is separated from Bl by a
deep sulcus and notch; in C57BL these two cusps are scarcely separated from
142
H. GRUNEBERG
each other anteriorly; BALB/c is intermediate in this respect. Cusps Bl and B2,
as seen in buccal view, are clearly separated from each other by a notch in CB A
and C57BL; that notch tends to be shallower in BALB/c, and in A it is sometimes
all but absent. A peculiarity of the A strain is the fact that the ledge which
continues Bl downward and posteriorly (and which may be regarded as a
cingulum) is more marked than in the other strains; it often shows variable
nodules and shallow extra cusps along its length; in Text-fig. 5, the A tooth has
such a nodule near the posterior end of B2.
C57BL
CBA
2 mm.
TEXT-FIG.
5. Buccal views of left mi from four inbred strains. Same animals as in text-figs. 2
and 3.
In the four strains examined, the second molars, both m 2 and m2, show no
very conspicuous inter-strain differences; in particular the extra cusp between
B2 and B3 of the m 1 in the A strain is not repeated in the corresponding position
of m 2 , nor is the curtain between these cusps in BALB/c repeated in m 2 . Moreover, in these four strains, variation in m 1 and mj is virtually confined to the
buccal surface whereas the lingual aspect is much less variable. Differences in
the size of m 3 and particularly of m 3 which culminate in the absence of many
of these teeth in CBA and less commonly in A have been investigated in some
detail (Griineberg, 1951) and will be discussed again below.
Genetics of the dentition in the mouse
143
Whereas the prestige of the dental crown is unchallenged, the morphology
of the roots is commonly regarded as almost a matter of accident. Comparison
of the inbred strains soon reveals that this attitude is quite mistaken. Certain
root patterns are as typical and constant within an inbred strain as the shape of
the crown. For instance, the C57BL strain differs from all the others in that the
anterior root of m 1 is particularly large and thrust out far forward; the root tips
are flared and compressed so that a fluted appearance is the result (Text-figs. 2,
5 and 13). At the other extreme is the corresponding root of the A strain which is
situated largely underneath the crown, which is much smaller and roundish in
cross-section and never shows any signs of flaring or fluting. Similarly, the
roots of mi (Text-fig. 5) are perfectly characteristic for the various strains. For
instance, a considerably reduced posterior root (mirrored in a similarly reduced
CBA
C57BL
BALB/c
2 nun.
TEXT-FIG. 6.
Crown views of the same teeth as in Text-fig. 5.
posterior root of m1) is characteristic of the A strain. Whereas usually the
posterior root of nij is almost as long as the anterior root, in the BALB/c strain
it is nearly always considerably shorter than the anterior one. It thus appears
that the morphology of the roots is much more independent than has commonly
been assumed, and that its characteristics are largely under genetical control.
This is a situation which could scarcely have been discovered except by the
comparison of inbred strains or, in man, by twin studies.
Mutant genes affecting the dentition
The main part of this paper is concerned with three genes which affect the
dentition as a whole. In each case, the dental involvement is part of a complicated pleiotropic pattern. The dental anomalies of the first of these genes,
Crooked-tail, are quite different from those of the other two, Tabby and crinkled
which are close mimics in other respects; they are also indistinguishable in their
effects on the teeth. Though we are confronted with two highly characteristic
10
144
H. GRUNEBERG
and specific types of dental morphology, even a tentative interpretation in
developmental terms, at this stage, seems premature.
Crooked-tail
The semi-dominant gene for Crooked-tail in the mouse (symbol Cd; Morgan,
1954; see also Griineberg, 1963), in CdjCd homozygotes, is responsible for
characteristic anomalies of the axial skeleton, an almost naked tail which lacks
proper tail rings, reduced eyes (microphthalmia) and anomalies of the incisors.
The gene arose as a spontaneous mutation in the A strain. On its original genetic
background, the lower incisors were greatly reduced and usually failed to erupt
altogether; if so, the upper incisors (which are of about normal size) are not worn
off by use and tend to grow in a circle (Text-fig. 7). More recently, on a different
Cd/Cd
TEXT-FIG.
7. Right incisors of a normal (+ / + ) and a Crooked-tail (Cd/Cd) $, 39 days old.
genetic background, the lower incisors are not quite so minute in size and often
erupt; they are, however, still much too small in relation to the upper ones. The
dental anomalies are not confined to the incisors. As first noticed by the present
author (unpubl.), the m 3 and particularly the m 3 are often absent, an anomaly
which has been studied embryologically by Grewal (1962). In the minority of
instances where these teeth are present, they are very small. The crowns of the
other molars show a characteristic morphology. The crown of m 1 is moderately
and that of m 2 strikingly reduced in size (Text-figs. 8 and 9). In both teeth, a narrowing of the neck gives the crowns a bulbous appearance. In m 1 , cusp 1 is more
erect than in the normal tooth and, in profile, is its most prominent feature. Cusp 2
is lower and cusp 3 somewhat reduced and turned in the lingual direction, as
best seen in crown view. Buccally, B2 and the accessory next to it are least
affected. B3 is moderately reduced, and Bl all but absent. Lingually, LI is
continuous with 1 without the marked depression which, in the normal tooth,
gives rise to the characteristic antero-lingual concavity as seen in crown view.
LI and L2 which are normally separated from each other by a deep valley have
little more than a nick to indicate their separate identities. The anterior and
Genetics of the dentition in the mouse
145
Cd/Cd
BUCCAL
LINGUAL
CROWN VIEW
1
8. Buccal, lingual and crown views of the left m of a normal (top row) and a CdJCd
mouse (bottom row), ?$ (litter mates), 21 days old. The extra cusp between B2 and B3
which is present in both teeth has nothing to do with the CV/gene; it is found in many animals
of the stock and is presumably a heritage from the A strain in which the gene arose.
TEXT-FIG.
lingual roots of m 1 are usually more or less completely fused with each other;
when part of the lingual root is separate, it can be seen that it is wider than
normal. As the CdlCd $ in Text-figs. 8-11 was not appreciably smaller than its
Normal
CdlCd
1 mm.
BUCCAL
TEXT-FIG.
LINGUAL
CROWN VIEW
9. Buccal, lingual and crown views of the left m2. Top row normal, bottom row
CdlCd. Same animals as in Text-fig. 8.
normal litter mate, the crowding of the roots under the crown cannot be ascribed
to shortage of space, as in the pituitary dwarf mouse (see below) where,
incidentally, the roots do not tend to fuse with each other.
In m 2 (Text-fig. 9), the situation is generally similar to that in m1. Whereas
146
H. GRUNEBERG
normally, cusp 3 is nearly as prominent as the (primary) cusp 2, inCd/Cd mice
it is strikingly flattened and scarcely projects above the level of the cusps which
surround it buccally, posteriorly and lingually. Cusps LI and L2 are represented
by a single very large cusp.
Normal
Cd/Cd
2 mm.
BUCCAL
LINGUAL
CROWN VIEW
10. Buccal, lingual and crown views of the left m^ Top row normal, bottom row
Cd/Cd (same animals as in Text-figs. 8 and 9). The accessory rootlet in the abnormal mouse
was present on both sides, but has probably nothing to do with Cd as it has not been seen
in any other individual. The shallow accessory cusps and nodules present buccally in both
teeth are probably a heritage of the A strain in which such features are common.
TEXT-FIG.
Normal
Cd/Cd
BUCCAL
LINGUAL
CROWN VIEW
TEXT-FIG. 11. Buccal, lingual and crown views of the left m 2 . Top row normal, bottom row
Cd/Cd (same animals as in Text-figs. 8—10).
Genetics of the dentition in the mouse
147
Morphologically, the lower molars are not so strikingly abnormal as the
upper ones, but the main features are similar. Thus the crown of m1 is moderately
and that of m2 strikingly reduced in size (Text-fig. 10 and 11). In m l5 LI is
scarcely separate from Bl except at the tip. Cusp 4 is present, but reduced in
size. In m2, Bl is reduced in size; though B3 and L3 are distinct elements which
do not tend to fuse with each other posteriorly, there is no recognizable cusp 4
to separate them from each other. The separation of the roots happens later
than normal, as in the upper molars. The Cd/Cd mouse shown in Text-figs.
8-11 lacked third molars altogether. Where such teeth are present, they are very
small, the crown pattern is simplified and the root single.
Tabby and crinkled
The sex-linked gene for Tabby (symbol Ta; Falconer, 1953) and the autosomal
recessive gene for crinkled (symbol cr; linkage group 14; Falconer, Fraser &
King, 1951) are close mimics with a highly characteristic pleiotropic pattern.
Both mutants lack guard and zigzag hairs in the adult coat; a conspicuous area
of naked skin is found behind each ear; it is due to the fact that zigzags only are
found here in the normal mouse. In both mutants the tail generally lacks hair
and tail rings, and it usually has some sharp flexures near the tip. Some of the
sinus hairs of the face are absent. It has recently been discovered that both
mutants also affect the teeth. Mr J. H. Isaacson, working in Dr Falconer's
laboratory, noticed that in both conditions abnormalities of the incisor teeth
are common. They may be smaller than normal, and sometimes an incisor is
lost altogether; malocclusion may necessitate artificial shortening of the incisors
to keep the animals alive. Mr Isaacson has kindly supplied me with the data
of Table 1 which show that the incidence of these dental abnormalities is considerably influenced by the genetic background on which the Ta gene finds itself;
he has also been good enough to turn the dental conditions over to me for further
study. The dental anomalies in the crjcr homozygote are indistinguishable from
those in Ta\Ta $$ and in Ta <$$. The following descriptions will thus be based
entirely on Ta.
The reduction of the incisors noticed by Mr Isaacson is part of an anomaly
which affects the dentition as a whole. In fact, the involvement of the molars is
generally far more striking than that of the incisors. The incisors of Tabby mice
may be of normal dimensions or nearly so. In some Tabbies, they are reduced in
calibre (Text-fig. 12), and it may be assumed that loss of an incisor will tend to
happen where this reduction in size is considerable. The incisors of the mouse,
like those of other rodents, are covered with enamel on their convex side only;
however, the enamel overlaps the flat lateral (buccal) side of the tooth, its margin
forming a fine line approximately parallel with the convexity of the tooth. In
Ta mice, the enamel covers more of the side of the tooth, both relatively and
absolutely; in the lower incisor, it even starts to overlap the medial side of the
148
H. GRUNEBERG
TABLE 1
Incidence of abnormalities of the incisors in Ta
backgrounds
on five different genetic
Ta/Ta $$ from a non-inbred stock were crossed with <$$ of five inbred strains. The teeth of
the Fi Ta $<$ were examined macroscopically and classified as 'normal' or 'abnormal'. Data
of Mr J. H. Isaacson (Edinburgh).
F\ from strain:
Normal
CBA
C57BL
RIII
JU
A
19
49
29
81
9
Abnormal
30
14
6
10
53
Total
49
63
35
91
62
% Abnormal
61-2
22-2
171
110
85-5
tooth. The increase in enamel cover is also found in those Ta incisors which are
not appreciably reduced in size.
All the molars are regularly and characteristically abnormal. The abnormalities
of the upper molars are less variable than those of the lower ones and may be
described first. The crown of m 1 is considerably reduced in size and shows
TEXT-FIG. 12. Right incisors of a normal and a Ta <$, 28 and 27 days old respectively.
a simplified cusp pattern. Instead of the usual three roots, there is a single
root whose composite nature is still detectable by its surface moulding
(Text-fig. 13). The three central cusps 1, 2 and 3 are present, but they are more
erect than usual. Buccally, B2 is present, but Bl and B3 have disappeared
completely. Lingually, the separation of LI from 1 is so shallow that in crown
view (Text-fig. 14) the concavity of the lingual and anterior border is completely
absent. Again, similar to Cd/Cd, the separation of LI from L2 is usually much
less complete than normal and may be almost absent.
The crown of m 2 is much less reduced in size than that of m 1 , but again there
is a single composite root. In the normal m2, cusp Bl is far smaller than B2
and often hardly detectable. In the m 2 of Ta mice, paradoxically, Bl is considerably increased and often reaches the height B2 and of LI with which it then
becomes continuous, as in Text-fig. 13. In such cases, the buccal aspects of m 1
Genetics of the dentition in the mouse
149
Ta
TEXT-FIG.
13. Buccal views of the right m1 and m2 of a normal (C57BL) & 65 days old (top)
and of a Ta <J, 27 days old (bottom).
Ta
Ta
2 mm.
TEXT-FIG.
14. Crown views of the same teeth as in Text-fig. 13.
and m 2 come to resemble each other much more than in the normal mouse. The
behaviour of m 3 is variable; often, it is absent altogether.
The lower molars are very variable, but a certain pattern clearly emerges. In
the normal mouse (Text-fig. 16, a), m1 is far larger than m2. In Ta mice mj is
reduced to a very variable extent. Commonly, as in Text-fig. 15, mx is down to
the size of m 2 which itself is not appreciably reduced. The root of mx is composite
and still slightly forked basally (depending on the degree of reduction of the
crown of m l5 there may be all intergrades between a double and a single root
(see Text-fig. 16, b and c)). In this case, ml and m 2 are not only similar in size,
but also in their cusp pattern. In both teeth, the posterior end is formed by a
large cusp which corresponds to L3 + B3, and cusp 4 is completely absent. In
both teeth, the largest cusp is L2 which is less erect than normally and points,
150
H. GRUNEBERG
somewhat aggressively, upward and forward. It is continuous with a ridge
corresponding in position to B2. A proper B2 usually cannot be made out in a
Ta m 2 . Both teeth in Text-fig. 15 may be interpreted as consisting essentially of a
larger anterior and a smaller posterior cusp each of which reaches from the
lingual to the buccal aspect of the tooth. Both mi and m2 have lost material
both anteriorly and posteriorly. Anteriorly, mj has lost LI and Bl and possibly
B2; and m2 has lost Bl and possibly B2. Posteriorly, both teeth have lost cusp 4,
and this feature is constant for both regardless of any other variation (see, e.g.,
Text-fig. 16, b and c) as is the loss of LI in mx and that of Bl in m2.
1 mm.
BUCCAL
TEXT-FIG.
LINGUAL
CROWN VIEW
15. Right nix and m2 of a Ta 3, 78 days old. Medium degree of reduction of m^
Turning now to some variants of this theme, mi in Text-fig. 16, b is still the largest
and mx in c is definitely the smallest of the molars (still more reduced types of
ml are not rare). The main difference as compared with Text-fig. 15 is in the
anterior parts of mi where in b cusps Bl and B2 can still be made out though LI
is absent; whereas in c the anterior of the two cusps is losing its dominating
position. The main interest of Text-fig. 16 lies in the fact that it reveals the
existence of competitive relationships between neighbouring teeth. In b, where
m1 is only mildly reduced, m 2 is slightly and m 3 considerably smaller than normal;
in fact, in similar cases, slight reduction of mi tends to go together with complete
absence of m 3 . Conversely, in c, where mj is greatly reduced, m 2 is larger than
normal (the absence of certain cusps notwithstanding) and m 3 has become very
large and starts to resemble m2 in b; the most extraordinary feature is the fact
that this m 3 is beginning to develop a cusp B3 which is not part of the normal
Genetics of the dentition in the mouse
151
equipment of this tooth at all. The relationships shown in Fig. 16 are typical:
where mL is but slightly reduced, m2 and m 3 are smaller than normal and m 3
tends to disappear altogether. Conversely, where ir^ is very small, m 2 and m 3
are large and may exceed the normal dimensions of these elements.
Evidently, what is far less obvious in normal development, the size of m2 is a
limiting factor for the growth of m 2 and of m 3 . When mx is much reduced, m 2
2 mm.
16. Buccal views of m1} m2 and 1113, together with posterior views of 1TI3 normal to
its axis, a, normal (C57BL) $, 65 days old. b, Ta/Ta $, 26 days old, with slight reduction of
mi and marked reduction of m3. c, Ta <$, 27 days old, with strong reduction of mj, but
increased size of m2 and particularly of m3.
TEXT-FIG.
and m 3 are able to grow well beyond the size they reach in the presence of a
strong competitor. It is, of course, well known (Gaunt, 1955,1956) that growth,
morphogenesis, histogenesis and eruption of the mouse molars follows a time
sequence which starts with mj and ends with m3. Weakening of competition
may also explain one seemingly paradoxical fact which was mentioned above. In
Ta mice, cusp Bl of m 2 (normally small and sometimes rudimentary) is increased
in size to a greater or lesser extent (Text-fig. 13). Apparently in the Ta mouse,
152
H. GRUNEBERG
m 2 can realize growth potentialities which, in the normal mouse, are inhibited
by the larger m 1 .
It appears, then, that the ultimate fate of the Ta molars is determined by a
tug-of-war between two opposing forces. On the one hand, the Ta gene reduces
the size of the molars. This is most obvious in m 1 and m t which differentiate
first; but—provided the reduction of the first molars has not gone very far
(which is true for m 1 and sometimes for mj)—the reduction is also visible in
m 2 and m2 and in m3 and m 3 (which may disappear altogether). With stronger
reduction of m l9 weakened competition releases growth potentialities in m 2 and m 3
which tend to compensate for the size reduction due to the Ta gene and which, in
extreme cases, may even allow m 2 and m 3 to grow beyond the size found in the
normal mouse.
It should be mentioned that the degree of reduction of m2 tends to be about
the same on the right and left though sometimes the sides differ considerably.
The row of molars starts anteriorly in the normal position, but is shorter; the
teeth stand in close formation and without gaps, as in the normal mouse.
Despite all variations, the effects of the Ta gene, both in TajTa ?$ and in Ta <$£,
are highly characteristic; at least on the present genetic background (which is
heterogeneous) and in the somewhat limited sample examined, no first or second
molar could possibly be mistaken for a normal tooth. By contrast, some Ta\ + $$
show a most striking mixture of normal molars, Ta molars, and molars which
combine features of both types. Clearly, this is what would be expected on the
inactive-X hypothesis propounded by Lyon (1961). Whereas most of the previous
evidence for that hypothesis was based on coat colour variegation which, in
different genetic situations, can be brought about by other mechanisms, the
unique behaviour of the molars in some Taj+ $$ is strong prima facie support
for the inactive-X hypothesis. The phenomenon can, however, be made the
basis for a more exacting quantitative test of the hypothesis. Such investigations
are now in progress and will be reported elsewhere.
A search for additional genes affecting the teeth
In the absence of systematic knowledge concerning pleiotropic effects of genes
on the teeth, a general dental survey seemed indicated. As the genes in the mouse
with known major effects on the teeth all affect the skeleton and/or the skin and
fur, this lead was followed up; but other genes were also included for which
material was either available or could easily be obtained. The material inspected
(Table 2) includes forty-four major genes (43 loci), not counting the more usual
coat colour genes whose effects on the teeth (if any) would also have been
detectable. The preparations were scanned for major effects on the crowns of
the molars; in a number of cases, minor variants as described earlier on in this
paper were found in the mutants; in every instance, the examination of normal
litter mates (not included in Table 2) showed that the presence of the variant
Genetics of the dentition in the mouse
153
TABLE 2
Mutant genes inspectedfor dental anomalies. Symbols and numbers
examined in brackets
Mutant
Bent-tail (Bn; 4)
Brachypodism (bp/bp; 6)
Brachyury (T/+; 2)
Brindled (Br/+; 2)
Caracul (Ca/+; 2)
Curly-tail (ct/ct; 3)
Danforth's short-tail (Sd/+ ; 4)
Deafness (dn/dn; 2)
Dominant spotting (1VV/+ ; 4)
Dreher (dr/dr; 2)
Fidget (/?//?; 6)
Flexed-tail (///"; 2)
Fuzzy (fz/fz; 2)
Hairless (hr/hr); 2)
Hairless-rhino (hrrl'/hrrh; 2)
Hairloss (A/////; 2)
Hydrocephalus-3 (hy-3/hy-3; 1)
Naked (A7+; 2)
Nude (nu/nu; 1)
Ocular retardation (or/or; 6)
Oligosyndactylism (Os/+ ; 2)
Patch(P/j/+;4)
Pintail (/»//+; 5)
Pituitary dwarf (dwjdw; 7)
Pudgy(/?«//?w;6)
Pygmy(/7g-//?g;6)
Ragged (Ra/+; 2)
Rex (J?e/+ ; 2)
Rough (rojro; 2)
Shaker
Shaker with
with syndactylism
syndactylism (sy/sy); 11)
Shaven (Sha/Sha; 2)
Short-ear Oe/se; 4)
Spinner (^r/j/-; 1)
Syndactylism (sm/sm; 3)
Tail-kinks (tk/tk; 3)
Tail-short (7V+; 5)
Tremor (tr/tr; 3)
Truncate (tc/tc; 1)
Undulated (un/un; 4)
Vestigial-tail (v//vf; 4)
Waved-2\ , ^, ^ ,
T
-J r [yva-2 wa-2; lu, 2)
Luxoid J
WhiteCM/^'/M/11"1^)
could not be ascribed to the mutant gene as such. As in many instances the
teeth were inspected in situ, anomalies of the roots not accompanied by changes
in the crowns may have escaped detection.
With one comparatively trivial exception, the general dental survey summarized in Table 2 has been completely negative. None of the genes had effects
sufficiently striking to attract the attention of the present author. The exception
is the gene for pituitary dwarfism (dw). As is well known, the ever-growing
CBA
5 mm.
TEXT-FIG. 17. Left incisors of a normal (CBA) and a pituitary dwarf mouse, 59 and 64 days old
respectively.
154
H. GRUNEBERG
incisors of rodents grow in a spiral the radius of which increases with the growth
of the animal. Small animals like pituitary dwarfs thus have smaller incisors
than normals of the same age (Text-fig. 17). On the other hand, the growth of
the molar crowns of pituitary dwarfs is virtually complete by the time the general
growth of these animals slows down about a week or so after birth. Hence the
molar crowns of pituitary dwarfs are of normal size (Text-fig. 18). But by the
time the roots are forming, the pituitary dwarfs are already markedly smaller
than normal. Hence the animals end up with normal crowns resting on reduced
roots.
MAXILLARY
MAND1BULAR
CBA
2 mm.
TEXT-FIG.
18. The left molars of the same two animals as in Text-fig. 17. Note that the dwarf
animal has molar crowns of normal size, but reduced roots.
DISCUSSION
Comparatively little is known about the development of the molar crowns in
mammals; the rather scattered literature has been summarized by Butler (1956)
to whose review the reader may be referred for more details. Enamel and
dentine is formed by two layers of cells, ameloblasts and odontoblasts, which
are at first separated from each other only by the basement membrane of the
ameloblasts, the membrana praeformativa. The enamel-dentine junction thus
corresponds to the final configuration of the membrana praeformativa, and the
shape of the crown differs from it only to the extent to which the thickness of the
enamel varies from point to point. With this qualification, the development of
the molar crown is the process which transforms the simple shape of that
membrane in the bell stage into the complicated surface with its cusps, ridges and
sulci in the finished crown. Generally speaking, the tip of the primary cusp is
formed by the apex of the inner enamel epithelium where mitotic activity comes
to an end; growth continues on the slopes of the cusp. The tips of secondary
cusps are again areas of the inner enamel epithelium where active growth ceases;
Genetics of the dentition in the mouse
155
in the intervals between cusps continuing mitotic activity leads to the formation
of gradually deepening valleys and sulci. Secondary cusps thus form on the
slopes of the primary cusp, or at its base. The ridges and crests which often
connect the cusps, according to Butler (1956) can largely be explained as 'lines
of tension set up in the epithelium by its unequal growth'. Taken as a whole,
the shape of the crown is thus the result of localized active growth processes
and of mechanical stresses thereby set up in the inner enamel epithelium.
The development of the mouse molars has been studied in detail by Gaunt
(1955, 1956, 1961, and personal communication). In m1, a median longitudinal
ridge is first to form, and near its midpoint cusp B2 develops as the primary cusp,
to be followed rapidly on its lingual side by cusp 2 which becomes the dominating
cusp of the crown. Almost simultaneously, cusp B3 arises to complete the
trigon. Cusps LI and L2 form on the lingual side as the crown border bulges
and also cusps 1 and 3 form at the same time. The development of m 2 is similar
to that of m1, except that cusp 1 does not form. In the lower molars, the midregion (L2 and B2) differentiates first; in m t this is followed about simultaneously
by the formation of LI and Bl (of which LI comes to occupy a median position
and partly merges with Bl), and of L3 and B3; cusp 4 arises late in development.
Events are similar in m2, except that LI is not formed.
The variations described in this paper involve both the original trigon and
areas of the crown which develop later. For instance, in m1, the inter-strain
differences are largely in the region of B2 and B3 and thus in the precincts of the
trigon, but also near the base of cusp 1 which forms late in development. In
m l5 the most marked inter-strain differences involve the degree of coalescence
between LI and Bl and variations in the buccal cingulum, all of which are late.
The same in principle applies to the effects of the major genes. In Cd, the
primary cusps are least affected. In Ta, most suppressed cusps develop late (in
itij, cusps LI and Bl and 4; in m 2 , Bl and 4; in m 1 , Bl), but the missing cusp B3
is a member of the original trigon both in m 1 and in m 2 . The paradoxical increase
of Bl in m 2 found in Ta mice may be due to a relaxation of competition by m 1 ;
but Bl is not increased in Cd/Cd mice although m 1 is reduced to a similar extent.
The data presented in this paper give evidence both of independence and of
interdependence of neighbouring molars. Independent or autonomous behaviour
is indicated in Ta/+ $? where phenotypically normal and Ta teeth may stand
next to each other without apparently influencing each other's development.
This phenomenon will be discussed in more detail in a later publication. Interdependence of molars is reflected in competition. Normally, it appears, the firstformed molars (m1 and m2) limit the size of the rest; when, as in some Tabby
and crinkled mice, ml is greatly reduced, growth potentialities in m2 and m 3 may
be released which are not realized in normal development. The existence of
such competitive relationships had been suspected as long ago as 1951 when the
present author pointed out that in CBA mice in which m 3 is much reduced, m^ is
larger than normal.
156
H. GRUNEBERG
When the size of m 3 and particularly of m 3 is reduced below a certain critical
level, the tooth tends to be absent altogether (Griineberg, 1951). This is true
whether reduction is due to a multifactorial situation, as in CBA and A, or
whether it is brought about by the action of a single 'major' gene such as Cd.
As shown in this paper, the genes Ta and cr have similar effects. In CBA and in
CdjCd mice, missing third molars are originally represented by tooth germs
which do not grow beyond the cap stage and then regress (Grewal, 1962); the
same is presumably true for the new instances for which no direct embryological
evidence is available yet.
The development of the roots is partly determined by the size of the crown, as
in Ta where mj may show all intergrades between one and two roots in conformity with the size of the crown, and similarly in m 3 ; for m3, the same is also
seen in the inter-strain difference between CBA and C57BL where in CBA
reduction of the crown leads to simplification of the root (Griineberg, 1951). The
development of the roots is also influenced by the size of the jaw, as in the
pituitary dwarf mouse where reduction of roots goes together with crowns of
perfectly normal size. However, the striking inter-strain differences in root
development cannot be ascribed to either of these causes and show that the
morphology of the roots is also more directly under genetic control. This
finding was unexpected, and the various inbred strains present excellent material
in which the developmental basis of these genetic differences can be studied. As
root development of all mouse molars is entirely post-natal, an experimental
approach may be practicable.
In addition to those described in this paper, there are three other dental
conditions in the mouse due to 'major' genes. In the grey-lethal mouse (gl;
Griineberg, 1937), the involvement of the dentition is secondary to a failure of
secondary bone absorption, and the same down to details is true in the
microphthalmia syndrome (mi; Hertwig, 1942; Griineberg, 1948; Freye, 1956).
The dental involvement in the screw-tail syndrome (sc; MacDowell et al., 1942)
has unfortunately not been studied in detail, and the gene is now extinct. The
occurrence of somewhat irregular extra lower incisors described by Danforth
(1958) is probably due to the combined action of several genes and thus forms a
link with the multifactorial situations which determine size (and indirectly
presence or absence) of the third molars in CBA and A (Griineberg, 1951).
Presumably the inter-strain differences described in this paper have a similar
multifactorial basis though, in the absence of genetical data, this cannot be
more than a supposition.
For reasons of space, we cannot discuss here in detail inherited dental
anomalies in other animals. But the incisorless rat (id) investigated in considerable detail by a team of American investigators may be mentioned (for a review
see Griineberg, 1963); similarly, in the rabbit, inherited dental variants including
the occurrence of extra upper incisors have been described by Nachtsheim
(1936).
Genetics of the dentition in the mouse
157
The analysis of the abnormal growth processes in the dentitions of Cd, Ta
and cr mice will require direct embryological studies, and speculations based on
the finished product may be dispensed with. Nor would it be useful, at this
stage, to speculate on the ways in which the dental manifestations of these genes
fit into their complicated pleiotropic patterns. The fact may be noted that all
three mutants have naked tails with defective tail rings, whereas none of the
genes in Table 2 has this effect: whether this is more than a coincidence is a moot
point.
Finally, a word of apology may not be amiss. The facts reported in this paper
are new. But the conclusions drawn from them are probably largely well known
to students of mammalian palaeontology, taxonomy and dentistry with whose
writings the present author is not familiar. In so far as this should be the case,
confirmation from a different set of observations will do no harm. Where
conclusions have been reached which are at variance with accepted concepts,
they stem from material which is open to genetical and, it is hoped, presently to
embryological experimentation.
SUMMARY
1. Comparison between some inbred strains of mice revealed the existence
of several inherited variations of the crowns of the first molars. Similar variants
are also present in some wild mice. The inbred strains also differ characteristically
in the morphology of the roots; these variations cannot be regarded as secondary
to size or morphology of the crowns.
2. Three genes are described which affect the dentition of the mouse as a
whole. The Crooked-tail (Cd) gene greatly reduces the size of the lower (but not
of the upper) incisor. The first molars are moderately and the second molars
considerably reduced in size; the third molars are usually absent. There are
characteristic changes in the cusp pattern of the molars.
3. The genes for Tabby (Ta) and for crinkled (cr) which are close mimics in
other respects also product indistinguishable effects on the teeth. Both incisors
are affected, but often only slightly; laterally they are more widely covered with
enamel even if of about normal size. Reduction of the molars tends to be more
extreme in the first than in the second and third molars (though the latter may be
absent). The most variable tooth is m x ; normally by far the largest in the row,
it may be reduced to become the smallest. If so, m 2 and m 3 tend to grow even
larger than in a normal mouse, a sign that in normal development n^ competitively inhibits the growth of the later formed molars. The cusps of all molars
are characteristically reduced, but the pattern is quite different from that produced
by Cd.
4. A general survey of over forty different mutants in the mouse has failed to
reveal additional genes with major effects on the teeth.
158
H. GRUNEBERG
RESUME
Genes et genotypes affectant les dents de la souris
1. Une comparaison entre quelques lignees consanguines de souris a montre
l'existence de plusieurs variations transmises par heredite dans les couronnes
des premieres molaires. Des variations semblables se trouvent aussi chez
quelques souris sauvages. Les lignees consanguines presentent aussi des
differences caracteristiques dans la morphologie des racines; ces variations ne
peuvent etre regardees comme des consequences de la taille et de la morphologie
des couronnes.
2. Trois genes qui affectent la dentition de la souris comme un tout sont
decrits. Le gene Crooked-tail (Cd) reduit beaucoup la taille de l'incisive inferieure
(mais non de la superieur). La taille des premieres molaires est moderemment
reduite, celle des secondes molaires Test considerablement et les troisiemes
molaires sont generalement absentes. II y a des changements caracteristiques
dans la disposition des cuspides de ces molaires.
3. Les genes des mutations Tabby (Ta) et crinkled (cr) qui s'imitent etroitement
sous d'autres rapports, produisent aussi des effets que Ton ne peut distinguer
sur les dents. Les deux incisives sont affectees, mais souvent tres peu; lateralement elles sont d'avantage recouvertes d'email meme si elles sont a peu pres de
taille normale. La reduction des molaires tend a etre plus accentee sur les
premieres que sur les secondes et les troisiemes (bien que ces troisiemes puissent
etre absentes). La dent qui varie le plus est m^; normalement elle a de beaucoup
la plus grande couronne mais elle peut etre reduite a avoir la plus petite. Dans ce
cas m 2 et m 3 tendent a croitre d'avantage que chez une souris normale, c'est le
signe que dans le developpement normal ml inhibe d'une maniere competitive
la croissance des molaires formees plus tard. Les cuspides de toutes les molaires
sont reduites d'une facon caracteristique mais leur distribution est assez differente
de celle produite par Cd.
4. Une revue generate portant sur quarante mutants differents chez la souris
n'a pas manifeste l'existence d'autres genes ayant des effets majeurs sur les dents.
ACKNOWLEDGEMENTS
The author is greatly indebted to Dr D. S. Falconer and to Mr J. H. Isaacson (Edinburgh)
for turning the genes of Ta and cr over to him for further study, for the data of Table 1, and
for supplying many of the mice listed in Table 2. Some preparations were also kindly made
for him by Dr A. G. Searle (Harwell). For permission to examine some wild mice from
Hampshire he is indebted to Dr R. J. Berry, and for assistance in various ways to Dr Gillian
M. Truslove and to Miss Jean Gray. His special thanks are due to Mr A. J. Lee for the accurate
and beautiful drawings which illustrate this paper.
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{Manuscript received 28th April 1965)
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