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Hypotelorism in trisomy 1-producing mice.

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THE ANATOMICAL RECORD 206:307-312 119851
Hypotelorism in Trisomy 1-Producing Mice
HELMUT v DOMARUS
Hospital for Kiefer- und Gesschtschirurgie, Medszsnische Hochschule
Lubeck, 0-2400Lubeck, Federal Republic of Germany
ABSTRACT
Trisomy 1 embryos in mice are smaller in all dimensions,
showing a developmental retardation as compared with euploid mice. Very
rarely the trisomic embryos develop a typical hypotelorism with holoprosencephalon and missing olfactory nerves. Corneal distances, angles between the
optic nerves and further microscopic examination showed no intermediate
forms between the trisomy 1 embryos and the rare trisomy 1 embryo with
hypotelorism. There seems to be a threshold, beyond which the major developmental derangement occurred. This is an experimental model showing parallels to the occasional varying phenotypes in human trisomies.
Laboratory mice normally have 20 pairs of
acrocentric chromosomes. Some feral mice,
however, show a number of metacentric chromosomes originated from two acrocentric
chromosomes which fused at the centromere
in the form of a Robertsonian whole arm
translocation (Gropp and Winking, 1981).
Seven pairs of such metacentric chromosomes were found in M. m. poschiauinus in
southeastern Switzerland (Gropp et al., 1970).
By appropriate crosses in the Lubeck laboratories they produced males with two defined
metacentric chromosomes as for example Rb
1Bnr with the arms of chromosomes 3 and 1
and Rb 10 Bnr with the arms of chromosomes
10 and 1. Due to segregational meiotic disorders (Fig. l), when crossed with NMRI-laboratory mice bearing all acrocentric chromosomes, they produced trisomies and monosomies (Gropp, 1975).
MATERIALS, METHODS, AND RESULTS
In a personal series of 248 embryos from
this trisomy 1-producing model, we observed
by chromosome analysis 53 embryos with trisomy 1and 195 euploid embryos. The female
NMRI mice were mated overnight with
males which had the metacentric chromosomes Rb 1 Bnr and Rb 10 Bnr (Fig. 1).The
mice were kept a t a temperature of 20-22"C,
humidity 50-6070, a 12-hour daylnight
rhythm from 6 AM to 6 PM, and fed water and
food ad libitum. Gestational day 1 started on
the morning of a vaginal plug. The embryos
had to be investigated at day 13 and day 14
as embryos of trisomy 1 die after this period.
1983 ALAN R LISS. INC
The investigation was carried out to examine
possible malformations in trisomy 1 embryos. Trisomic embryos were smaller in all
dimensions, showing only a developmental
retardation as compared to the euploid embryo (v. Domarus, 1977).
One of the 53 trisomic embryos showed a
marked hypotelorism with a median supraorbital proboscis (Fig. 2a,b). This observation is repeatable as another four trisomy
1 embryos with hypotelorism were observed
in the same Lubeck laboratories' in the early
seventies in a series of approximately 100
trisomic embryos used for other purposes.
This event therefore occurs in a roughly estimated 2 4 % of the trisomic embryos.
Measurements of corneal distances taken
from standardized photographs were shorter
than in euploid embryos but were congruent
with other dimensions of the trisomic embryos, therefore demonstrating nothing but
the developmental retardation (v. Domarus,
1977).
Having ruled out a possible position effect
(v. Domarus and Louton, 19811, we selected
from all viable trisomic embryos (n = 33) six
pairs of euploid and trisomic embryos with
the aid of random figures, each pair from one
litter. On horizontal histological sections in
the plane of the optic nerves we measured
the angle between the optic nerves anterior
to the chiasm (Fig. 3a,b).
'Personal communication: Gropp and Zimmerrnann, Institut
fur Pathologie der Medizinischen Hochschule Lubeck, F.R.G.
Received November 5, 1982; accepted March 22, 1983.
308
H. v. DOMARUS
a)
3
-
3
1
TRISOMY 1
Fig. 1. a ) Diploid male with the two fused chroinosomes 311 (~ Rb 1 Bnr) and l0il I = Rb 10 Bnr). Only six
chromosomes out of diploid set 2 11 = 40 shown i n the
diagram. b) Two out of foul possible haploid sperm segregants. c) Normal female, haploid set. Only two sets of
10
1
10
MONOSOMY
three chromosomes each out of n = 20 shown in the
diagram. d) When crossing b with c, trisomics and monosomies can be produced. The simultancously produced
euploid embryos are not included in the diagram (see b).
Fig. 2 . Trisomy 1 embryo, day 14, with marked hypotelorisni and il median proboscis. Lateral
(a) and frontal (b) views.
HYPOTELORISM IN TRISOMY 1 MICE
Fig. 3. Horizontal microscopic sections in the Plane of
the optic nerves of an euploid (a) and a nonhypoteloric
trisomy 1 embryo 6)to meamre the angle between the
optic nerves anterior to the chiasm. Both embryos, day
14. There are no detectable defects of the main anatomic
309
structures in the trisomic embryo. Eye (l), optic nerve
(2),diencephalon ( 3 ) ,pituitary gland (41,internal carotid
artery (5), trigeminal ganglion (6),upper cardinal vein
(7), “anlage” of the ear (8).
310
H. v DOMARUS
Repeated measurements of the same angles differed between zero and four degrees.
The figures in Table 1 are mean values. As
seen in Table 1, there was not the slightest
hint of smaller angles for the trisomic embryos, which would have indicated a possible
tendency towards hypotelorism. Therefore we
did not pursue these measurements with a
larger number of embryos. Furthermore, the
olfactory nerves were well differentiated in
the trisomic embryos.
Serial microscopic sections of the hypotelorism embryo showed a n optic stalk only on
one side (Fig. 4).Autolytic signs were minimal, although the embryo was probably already avital when rescued. There was one
holencephalon (Fig. 5 ) , and a n olfactory bulb
was not detectable.
DISCUSSION
The development of malformations depends on the genetic background of the animals used and can differ from one strain of
laboratory mice to another (fiasler, 1968).It
is quite possible, therefore, that producing
TABLE 1. Angle between optic nerues anterior to
chiasm'
Euploid
Trisomic
Euploid
Trisomic
Euploid
Trisoniic
Euploid
Trisomic
Euploid
Trisomic
Euploid
Trisomic
Embryo no.
Angle hetween optic nerves
2,17915
2,17914
2,22015
2,22016
2,22418
2,22414
2,23211
2,23212
2,23411
2,234110
2,242/13
2,24213
145O
147"
147"
157"
159.5"
159.0"
162
160"
153"
155"
152.5"
154.5"
'Comparison hetween euploid and Lrisomic embryos each pair
from same litter. pairs selected from vital t r i s o m i c embryos with
aid of random figures.
trisomy 1 embryos in another strain of mice
could increase or decrease the number of hypoteloric embryos.
Hypotelorism has to our knowledge not
been described in laboratory mice. In this
experimental model it did occur but as an
Fig. 4. Trisomy 1 embryo, day 14, with hypotelorism. Eye (11, optic stalk (2)and diencephalon ( 3 )
HYPOTELORISM IN TRISOMY 1 MICE
311
Fig. 5 Trisomy 1 cmbryo, day 14, with hypotelorism showing holoprosencephalon. Prosen
cephalon (l),dicncephalon ( 2 ) .
exception and in trisomic embryos only, somies allows the study of endogenous terawithout any intermediate forms. Neither the togenesis. Therefore, as one of many other
angle of the optic nerves (Table 1) nor the examples, we see a parallel between the occasional arrhinencephaly and cyclopia in huintercorneal distances or a possible lacking
“anlage” of the olfactory nerves (v. Domarus, man trisomy 13 (Buhler et al., 1962; Miller
et al., 1962; Singh et al., 1974; Warkany,
1977) gave any clues toward a development
of cyclopia or hypotelorism in the trisomy 1 19711, and our results, which throws some
light on the variation of phenotypes in huembryos, which seems to indicate a threshold
man trisomies.
for the development of hypotelorism.
Apart from the typical outer aspect our
LITERATURE CITED
embryo showed a holencephalon and missing
olfactory nerves on microscopic sections, fur- Buhlcr, E.. I. Bodis, B. Rossier and G. Stalder (1962)
Trisomie 13-15 mit Cebocephalie. Ann. Paediatr.,
ther underlining the very close resemblance
(Basel) 199:198-205.
with the human pathology (De Myer, 1975). De Myer, W. (1975) Median facial malformations and
We therefore believe that this is experimentheir implications for brain malIiiimations. In: Morphogenesis and Malformation of Face and Brain. D.
tal evidence that a trisomy does favor the
Bergsma, ed. Alan R. Liss, Inc., New York, pp. 155development of rare spontaneous malformations. No other malformations but hypotelo- v. 181.
Domarus, H. (1977) Morphologische Befunde der
rism were found in trisomy 1 embryos. AlKopfregion bci der Trisomie-l der Maus. Habilitationsschrift Lubecli, pp. 1-111.
though hypotelorism occurred only very occasionally, there seems to be a strong link v. Domarus, H., and T. Louton (1981) The position effect
of embryos in trisomy-l producing mice. Teratology,
between trisomy 1 and this particular mal24,315-319.
formation. In contrast to the experiments Gropp, A . (1975) Chromosomal animal model of human
disease. Fetal trisomy and developmental failure. In:
with exogenous teratogenic factors (X-rays,
Teratolo~y,Trends and Applications. C.L. Berry and
corticosteroids, vitamin A), this model of tri-
3 12
H. v DOMARUS
D.E. Poswillo, eds. Springer-Verlag, B e r l i d e i d e l bergmew York, pp. 17-33.
Gropp, A., and H. Winking (1981) Robertsonian translocations: Cytology, meiosis, segregation patterns and
biological consequences of heterozygosity. Symp. Zool.
SOC.
Lond., 47:141-181.
Gropp, A,, U. Tettenborn, and E. v. Lehmann (1970)
Chromosomenvariation vom Robertson’schen Typus
bei der Tahakmaus, M. poschiavinus und ihren Hyhriden mit der Laboratoriumsmaus. Cytogenetics, 9:923.
Miller, J.Q., E.H. Picard, M.K. Alkan, and P.S. Gerald
(1962) Neurologic manifestations of 13-15 trisomy: A
chromosome abnormality in arrhinencephaly. Trans.
Am. Neurol. Assoc., 87:51-56.
Singh, D.N., R.A. Wiscovitch, R.A. Osborne, and G.R.
Hennigar (1974)Partial trisomy 13 in a case of cyclopia
with 13114 translocation. Clin. Genet., 5,218-222.
Trader, D.G. (1968)Pathogenesis of cleft lip and its relation to embryonic face shape in AIJ and C 57 BL
mice. Teratology, 1:33-50.
Warkany, J. (1971) Congenital Malformations. Year Book
Medical Publishers, Chicago, pp. 201-206.
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