CYTOPLASMIC INHERITANCE OF A CELL SURFACE ANTIGEN IN THE MOUSE

Copyright 0 1983 by the Genetics Society of America

CYTOPLASMIC INHERITANCE

OF A CELL SURFACE ANTIGEN

IN THE MOUSE

KIRSTEN FISCHER LINDAHL A N D BARBARA HAUSMANN Basel Institute for Immunology, Basel, Switzerland

Manuscript received June 25, 1982 Revised copy accepted November 4,1982

ABSTRACT

Mta is a cell surface antigen of the mouse and serves as a target for specific T killer lymphocytes. Using a killer cell assay, the antigen has been found in 72 strains of laboratory mice and, with one exception, in all tested samples of mice caught in the wild or bred from such, including Mus molossinus, Mus castaneus and Mus spretus. Five strains of rats, non-inbred NMRI mice, most substrains of NZB mice and the closely related strain NZO are negative for Mta. In reciprocal FI crosses between several Mta+ and two Mta- strains, the antigen is maternally transmitted; that is, Mta+ females bear only positive offspring, whereas Mta- females bear only negative offspring, regardless of the genotype of the male. Since 34 foster-nursed mice had the Mta type of their genetic mothers, the factor that determines expression of Mta must be transmitted before birth and not via the milk. The cytoplasmic genes of Mta+ strains have been combined with the chromosomal genes of Mta- strains, and vice versa, by repeated backcrossing. All progeny retained the Mta type of their maternal lines. Thus, the Mta type is determined solely by maternal inheritance and is not influenced by chromosomal genes. We found no evidence of incompatibility between the cytoplasmic factors and nuclear genes of Mta- and Mta+ strains.

OST

strains of mice carry the cell surface antigen Mta. It can be detected

M

by cytotoxic T lymphocytes raised in one of the rare negative strains. Mta

is expressed throughout life and has been found

on all lymphoid tissues, on

fibroblasts, and on a variety of tumor cell lines. On the basis of crosses involving

the Mta- strain

NZB

and Mta+ strains C58/J,

BALB/c

and

A . C A ,

we concluded

that Mta

is

maternally transmitted

(FISCHER

LINDAHL,

BOCCHIERI

and

RIBLET

1980).

Here we survey the distribution

of

Mta types among various strains of

mice and rats, and we also test how general the maternal transmission

is,

whether Mta is passed by the milk, and whether the Mta type is influenced by

chromosomal genes.

MATERIALS AND METHODS

484

K. FISCHER LINDAHL AND B . HAUSMANN

Kettering Institute for Cancer Research, New York, N. Y. DR. J. KNIGHT, MRC Immunopathology Research Unit, University of Otago Medical School, Dunedin, New Zealand, sent samples of NZ mice, designated /OU in this paper. ICR/Swiss mice were obtained from DR. K. BURKI, Laboratory of Cell Differentiation, University of Geneva, Switzerland. NFS/N mice came from the animal colony of Ciba-Geigy, Basel, Switzerland. DDK mice were a gift from DR. J.-L. GUENET, Institut Pasteur, Paris, France, and STU mice from DR. W. SCHAFER, Max-Planck-Institut fur Virusforschung, Tubingen, Germany.

Wild mice: Mice caught in four different localities in Denmark were given us by DR. P. HJoRTH (P.H.), Institute for Molecular Biology, University of Aarhus, Aarhus, Denmark, together with mice bred from wild mice. These included Mus costaneus, originally from DR. V. CHAPMAN, Roswell Park Memorial Institute, Buffalo, N. Y., and the strains WID 75, WLA 76 and WPA 77, inbred by DR.

J.-

L. GUENET, Institut Pasteur, Paris, France, from mice caught in southern France. WLA 76 is of pure wild origin, whereas strains WID 75 and WPA 77 were produced by crossing wild males with laboratory females and backcrossing the female offspring to the wild males. From DRS. A. GKOPP and H. WINKING (G&W), Institute for Pathology, University of Liibeck, Liibeck, Germany, we obtained mice of strains CD, Mil 11, Zhadar and Mus spretus, all maintained in small but non-inbred colonies. DR. D. J. SCHENDEL, Institute for Immunology, University of Munich, Munich, Germany, sent us frozen spleen cells, prepared from mice caught for DR. D. BENNETT (D.B.), Sloan-Kettering Institute for Cancer Research, New York, N. Y.

Rats: Rats of both sexes, about 2 months old, were obtained from Full or given to us by DR. D. BELLGRAU, Basel Institute for Immunology. The Hooded Lister strain originates from Olac.

Breeding: F1 hybrids between NZB/Bom and NZW/CrBom were bred at Bom. All other crosses were made at this institute. In general, we used two females and one male per cage, and the same male was used for successive backcross generations. We carried two separate lines of each cross in parallel and sampled individuals from both lines, except for the backcrossing of DBA/ZJ to NMRI/ Bom, which was done in a single line. Females were picked for breeding from the first litter of each generation without previous typing for Mta. In the first backcross generation of DBA/Z to NMRI we selected albino females. In the backcrossing of NMRI/Bom to C57BL/6J, we selected agouti FI and black N1 females, thus ensuring homozygosity at the agouti locus (chromosome 2). From the N1 females we selected H-2*'* homozygotes (chromosome 17). The cervical lymph nodes were removed from anesthetized mice, cell suspensions were prepared, and binding of radiolabeled monoclonal antibodies specific for H-ZKh of C57BL/6J (KOHLER, FISCHER LINDAHL and HEUSSER 1981) and for H-Zq of NMRI/Bom mice (LEMKE et al. 1978, FISCHER LINDAHL, HAUSMANN and FLAHERTY 1982) was measured. All mice survived this operation.

Foster-nursing: Pregnant females were killed by cervical dislocation as close as possible to the end of term, and the fetuses were delivered by hysterectomy. They were cleaned and given to foster mothers whose own litters, born a day or two previously, were removed.

Torget cells. I. Mice: Cell suspensions were prepared from spleens (and occasionally lymph nodes) of individual mice and cultured for 2 days with 2 pg/ml concanavalin A (Con A). Before the assay the live lymphoblasts were purified by centrifugation over a Ficoll-Urovison cushion ( p = 1.077 g/ml), washed, and the fraction to be used as hot target cells was labeled with %r, all as previously described (FISCHER LINDAHL and HAUSMANN 1980).

Target cells. II. Rats: Lymph node cells were cultured as above, but with 8 pg/ml Con A, for 2 days. Before the assay they were washed three times in Hanks' BSS with 0.1 M a-methylmannoside, and then processed as mouse target cells. This treatment prevented nonspecific killing or inhibition and did not affect detection of Mta, as tested with mouse target cells.

CYTOPLASMIC INHERITANCE I N MICE

485

Before the assay the viable blasts were purified and labeled with 51Cr as required. They were excellent target cells with a low spontaneous release, and cells from standard inbred strains prepared in the same way typed as expected in the killer assay. Although the recoveries varied greatly (from fewer than 1 X

lo6

to 25 x IO6 blast cells out of 20 x IO6 cells frozen), cryopreservation appears to be a useful method of saving cells from rare mice for study in several experiments.

Killer cell assay: Mta- mice were primed with H-2-compatible Mtaf cells (2 x IO7 pooled spleen, lymph node and thymus cells in serum-free medium) by three intraperitoneal injections, given at least 3 wk apart. Their spleen cells were then restimulated in mixed lymphocyte culture with irradiated Mta+ cells for 5 days as previously described (FISCHER LINDAHL and HAUSMANN 1980), except that the medium contained only 10% (v/v) fetal calf serum. The effector cells were then harvested and assayed. Two combinations were used: NZB/Bom anti-NZB/Full (an Mta+ subline of NZB (FISCHER LINDAHL, BOCCHIERI and RIBLET 1980)) and (NMRI/Bom X C57BL/6)Ft anti-C57BL/6. For the direct test, the killer cells (from 3 x IO4, 1 x IO5 and 3 x

lo5

initial responder cells cultured) were mixed with 1 x I O 4 51Cr-labeled target cells in triplicate wells of round-bottom microtiter plates in 200 pl of RPMI 1640 with 10% fetal calf serum. For the competition tests, killer cells from 3 X

lo5

initial responder cells and 1 x

lo4

%4abeled target cells of known Mta type were mixed with excess unlabeled cells to be typed (usually 1.5 x

lo5,

3 x

lo5

and 6 x

lo5).

The hot target cells were chosen to differ from the stimulator cells, especially at H-2, to obviate any killing not specific for Mta, and positive and negative controls were included in each assay. The plates were centrifuged 5 min at 20 x g and incubated 3.5 hr at 37'. A sample of supernatant (100 pl) was then collected from each well and the amount of 51Cr released measured in a gamma spectrometer. Results are geometric means of duplicates or triplicates, expressed as a percentage of the maximum release in the presence of a detergent. Spontaneous release was measured from target cells incubated with medium alone. The 95% confidence limits were calculated using FIELLER'S theorem (FINNEY 1964).

RESULTS

Strain

survey: Table 1 lists 79 strains of laboratory mice that have been typed

for Mta to date. Since we have found that the sublines NZB/BlPt and its

derivative NZB/Full differed from other NZB mice (FISCHER

LINDAHL,

BOCCHIERI

and

RIBLET

1980), we obtained some NZ mice directly from Otago University.

Figure

1

shows the typing of these and other inbred and foster-nursed mice.

The cold target competition assay (Figure l a ) is our most stringent test for a

positive strain. If the cells share Mta with the 51Cr-labeled target cells, they will

compete for the killers and inhibit the release of 51Cr. It is apparent that NZC

and NZW are Mta+. The NZB and NZO strains originated from the same female

in 1948

(BIELCHOWSKY

and GOODALL

1970), and it is therefore not surprising that

both are Mta-. Negative typing results should be confirmed by a direct test

(Figure Ib), since a strain with a cross-reactive form of Mta

or a quantitative

difference in expression might not compete efficiently and could be falsely

scored as negative. Labeled NZO target cells were not affected by killer cells

specific for Mta, but they can be killed by cells specific for H-2" (not shown) or

Qed-lb, both antigens that NZO shares with NZW.

Strain Rb(6.12)3Sic carries a Robertsonian translocation chromosome derived

from a mouse caught in Sicily (GROPP

and WINKING

1981). NMRI females may

have been used in the process of isolating this chromosome, which could explain

their being Mta- (A. GROPP,

personal communication).

486

K.

FISCHER LINDAHL AND B. HAUSMANN TABLE 1

Laboratory mouse strains typed for Mta

Negative: NMRI/Bom, NMRI/Ico, NMRI/Han, NZB/BINJ, NZB/CrBom, NZB/Hz, NZB/Icr, NZB/Ola, NZB/OU, NZO/OU, Rb(6.12)3Sic

Positive: A.AL, A.CA, AKR/J, AU/Ssj, BALB.B, BALB.K, BALB/cByJ, BALB/cJ, BDP/J, BUB/ BnJ, B6.AK1, B6-H-Zk, B6.K1, B6.K2, B6-Tla", BlO.A(4R), BlO.A(JR), BlO.BR, BlO.CAS1, BlO,DZ(M504), BlO.DRB6.2, BlO.KPA42, BlO.KPA44, B1O.M. BlO.MOL1, BlO,RIII(71NS), BlO.S, BlO.WB, BlO.Y, CBA/J, CE/J, CJH/HeJ, CJH/Tif, CJH-H-Z", C3H.JK, CJH.Q, C J H S W , C57BL/6J, C57BL/lOScSr, C57L/J, C58/J, DBA/2, DDK, HTI, I/LnJ, I/LnReJ, I/St, ICR/Swiss, LG/J, LP/J, MA/MyJ, NFS/N, NIH/Ola, NZB/BlPt, NZB/Full, NZC/OU, NZW/CrBom, NZW/Ola, NZW/OU, P/ J, PL/J, RF/J, RIIIS/J, SEA/GnJ, SEC/lReJ, SJL/J, SM/J, ST/bJ, STU, SWR, WB/ ReJ, 129/01a

1969; FESTING

1979; MORSE

1981); all other tested descendants of that stock were

Mta+ (ICR/Swiss, NIH/Ola, NFS/N, RF/J, SJL/J and SWWJ).

Wild mice: The mitochondrial DNA of a broad sample of laboratory strains

was identical when analyzed with restriction enzymes, suggesting that the mice

were all derived from the same female ancestor

(YONEKAWA

et

al.

1980; FERRIS,

SAGE

and WILSON

1982). It is therefore not surprising that they also share a

maternally transmitted antigen. Wild mice, on the other hand, represent many

different maternal lines of inheritance. Yet, among 51 mice sampled from 17

locations and several species, we found only a single negative mouse (Table

2).

Strains WID 75 and WPA 77 have their genomes from wild mice, but their

maternal line from laboratory mice. They too were Mta+. When possible, the

mice were typed both by cold target competition and direct lysis. Some (WLA

76, Mil I1 and

Mus

spretus) inhibited Mta killing incompletely in all tests (Figs.

2

and

3),

even though they were clearly positive and could be killed directly.

This might be a sign that cells of these strains express less Mta

or, more

interestingly, have a cross-reacting form; however, from the few tests done, we

cannot exclude a random fluctuation in expression, which we see occasionally

also in our standard inbred strains. The finding of two positive and one negative

mouse from the same stock of

Mus castaneus is puzzling and requires further

study.

Rats: We tested cells from five strains of rats: Lewis (Figure

2),

F344,

DA, BN

and Hooded Lister. All were negative for Mta in both competition and direct

killing assays.

CYTOPLASMIC INHERITANCE IN MICE

None

B6-Tlaa

C581J

BALBlc

I I I

I

1 - 1

1 1 1 1

1 1

I

*

,

I -

DBA/2

f.

NMRl

# 2

al!E

I

1 ;

NZBlBom f.DBA/2

i

i

NMRllHan

-1

NZBlOU

NZClOU

NZOlOU

NZWlOU

I I

NMRll

Bom

1 . : I I I I I

I I

70-

60-

50-

40-

NZO/OU

T

_B6-T/aa

I

487

Ratio initial responders: targets

FIGURE 1.-Mta typing by cold target competition (a) and direct lysis (b). In (a) NZB/Bom anti- NZB/Full killer cells were assayed on 51Cr-labeled B6-Tla" target cells, and unlabeled competitors were added at a ratio of 30 cold to 1 hot target cell. In (b) the NZB/Bom anti-NZB/Fiill killer cells

(0--0) were titrated directly on labeled target cells from NZB/OU and B6-Tla". Killer cells specific for Qed-1" (O----O, CB6F1 anti-BIO.A(5R) (FISCHER LINDAHL, HAUSMANN and FLAHERTY 1982)) and Qed-lb (A--A, B1O.BR anti-C3H/HeJ (FISCHER LINDAHL and HAUSMANN 1980)) served as positive and negative controls. Means and 95% confidence limits of triplicates are shown; the 95%

488

K. FISCHER LINDAHL AND B. HAUSMANN

TABLE 2

Mice of wild origin typed for Mta

~

Species Location O + 8 Mta type Source" Ref.*

M. musculus Denmark

Bjertrup, near Aarhus 2 + 0

+

P. H.

Hov, near Aarhus 3 + 0

+

P. H.

Hgrret Skov, near Aarhus 2

+

1

+

P. H.

Ladby, Fyn 3 + 0

+

P. H.

M. domesticus United Kingdom

Isle of May Skokholm

Skokholm, SK/CamEi (F29) France

WID 75 (F7)'

Toulouse, WLA 76 (F11)

WPA 77 (F9)' ItaJy Milano, Mil I1 Cittaducale, CD YugosJovia Zhadar lsraeJ

' IS/CamEi (F35)

New York Dutchess County California

SF/CamEi (F22/23) Peru

Peru Atteck/Ei (F22)

0 + 3

+

0 + 6

+

2 + 0

+

0 + 2

+

2 + 1

+

1 + 1 +d

2 + 2 +d

2 + 0

+

3 + 0

+

2 + 0

+

0 + 2

+

2 + 0

+

2 + 0

+

D. B.

D. B.

Jax 1, 2, 3

P. H. P. H. P. H.

G&W 4

G&W 4

G&W 4

Jax 12

D. B

Jax 1, 2, 5

Jax 1, 2

M. molossinus Japan

Kyushu (F25) 4 + 0

+

Jax 6

M . castaneus Thailand 3 + 0 1-/2+ P . H .

M . spretus Portugal

Porto Covo 0 + 3 +d G&W 7

See Materials and Methods, section on Wild Mice.

*

References: 1, WALLACE 1971; 2, WALLACE 1981; 3, FERRIS, SAGE and WILSON 1982; 4, GROPP and

WINKING 1981; 5, S A G E 1981; 6, POTTER 1978; 7, WINKING, NIELSEN and GROPP 1980. Maternal line from inbred laboratory mice.

Incomplete inhibition, see text and Figures 2 and 3.

Foster-nursing: We have tested whole litters of mice delivered by hysterec-

tomy and foster-nursed by females of the opposite Mta type. Since these foster-

nursed mice retained the Mta type of their genetic mother in every case (Table

CYTOPLASMIC INHERITANCE IN MICE

489

a

I I I

15

30

60

70-

60-

50-

40-

n

b

10

20

40

Ratio competitors

:

targets

FIGURE 2.-Mta typing of mice bred from wild ancestors. In one experiment (a), NZB/Bom anti- NZB/Fiill killer cells were tested on labeled BG-Tla" target cells, in another (b) (NMRI/Bom X C57BL/6)Fl anti-C57BL/G killers were tested on labeled SJL target cells. Killing in the absence of competitors is indicated by the upper horizontal lines, spontaneous release by the lower lines. The competitors were NMRI/Bom (0---0), NZB/Bom (U----U), Zhadar

(e-.),

CD

(e--+),

Mil II

( c - W ) , Mus spretus (A--A), and Lewis rat (0--0). The cross-hatched area in panel (a) includes BG-Tla", CBH.Q, C57BL/6 and (C57BL/6 X A/J)Fl competitors, in panel (b) BG-Tla", (DBA/ 2 X NMRI/Bom)Fl, SJL, ST/bJ and 129/01a competitors.

communication), who exchanged newborns between NZB/Icr and BALB/c

mothers.

Repeated backcrossing: Apparent maternal transmission is no proof for an

extra-chromosomal mechanism. The direction of shell coiling in Limnaea

(PLAGGE

1938, cited by

GRUN

1976) and female sterility in Drosophila

(ENGELS

1979) are examples of characters with strict maternal transmission in the first

generation, but can be shown by repeated backcrossing to be determined by

chromosomal genes. We have therefore tested whether the same might not be

the case for Mta (Table

5).

490

90

m

Q)

(I)

a

Q)

-

!??

70

7

6

In

-

a

0

0

CI

-

50

8

30

60-

50-

40-

K. FISCHER LINDAHL AND B. HAUSMANN

a

I I

15

30

$0

701

b

3

0

7

15

30

60

Rat

io

competitors

:

targets

FIGURE 3.-Mta typing of wild mice by cold target competition. Results of two experiments are shown, each testing NZB/Bom anti-NZB/Full killers on labeled A.CA target cells. The upper horizontal lines indicate the killing in the absence of competitors, the lower lines the spontaneous release. The cross-hatched areas in both panels show the inhibition by cells of the inbred strains A.CA, B6-Tla", BlO.DRB62, BlO,RIII(71NS), BlO.WB, C3H.JK, C57BL/6, I/LnReJ and I/St. The strongest and weakest inhibitor among four (panel a) and seven (panel b) mice caught in Denmark are shown (A---A). The other symbols refer to NMRI/Bom (0---0), Mus castaneus (W--W),

WLA 76 (A--A) and Mus molossinus (O--O).

from a standard positive strain. The Mta type was immediately reversed when

a backcross male was mated to an NZB/Bom female. Similarly, the fourth

generation of DBA/ZJ backcrossed to Mta- NMRI/Bom males (96.9% NMRI

genes) and the fifth generation of NMRI/Bom backcrossed to Mta+ C57BL/6J

males (98.4% C57BL/6 genes) remained true to their female line.

CYTOPLASMIC INHERITANCE IN MICE

491

TABLE 3

Mta typing of Ft mice

Cross

(NZB/Bom x A.CA) (A.CA X NZB/Bom)

(NZB/Bom x SJL) (SJL X NZB/Bom)

(NZB/Bom X NZW/CrBom) (NZW/CrBom x NZB/Bom) (NMRI/Bom X NZB/Bom)

(NMRI/Bom x C3H.Q)

(NMRI/Bom x C57BL/6) (DBA/2 x NMRI/Bom)

Mice tested Mta type

(9 x 6 ) P + 6 -/+

-X+ 3 + 1 4/0

+X- 2 + 2 0/4

-X+ 2 + 2 4/0

+X- 2 + 2 0 /4

-X+ 5 + 0 510

+X- 5 + 0 0 / 5

-X- 3 + 1 4/0

-X+ 1 + 1 2 / 0

-X+ 1 + 1 2 / 0

+X- 2 + 0 0 / 2

TABLE 4

Mta typing of foster-nursed mice

Foster mother Mta tvpe Genetic mother Mta type Litter P

+

6 Mta tvpe

-/+

5 + 3 8/0

DBA/ZJBom

+

NZB/Bom -

5 + 3 8/0

DBA/2JBom

+

NZB/Bom

-

DBA/2JBom

+

NMRI/Bom - 3 + 7 10/0

NMRI/Bom

-

DBA/ZTBom

+

3 + 5 0/8

DISCUSSION

Expression of Mta is determined by a maternally transmitted factor. But the

relationship between the factor and Mta expression is as yet unknown. It is

possible that the positive strains receive the structural gene coding for Mta, or

that the negative strains have a maternally transmitted repressor of a chromo-

somal, structural gene shared by all mice. Our survey of laboratory and wild

mice shows that Mta+ is the prevalent type.

Mitochondrial DNA is a useful marker of the maternal line of inheritance in

mammals (HUTCHISON

et

al.

1974; HAYASHI

et

al. 1978; GILES

et

al. 1980;

YONEKAWA

et al. 1980). FERRIS,

SAGE and WILSON

(1982) recently concluded

from a representative panel of long established inbred strains that these were

descended from a single female, whereas several different restriction enzyme

patterns were found in the mitochondrial DNA of wild mice. Their analysis

also showed that SK/CamEi had the mitochondrial DNA of SF/Cam, and that

some

Mus

molossinus samples had the mitochondrial DNA of the long estab-

lished inbred strains. The number of independent maternal lines listed in Table

492

K. FISCHER LINDAHL AND B. HAUSMANN TABLE 5

Mto typing of successive generations of backcross progeny

Backcross

genera- Mice tested Mta type

Female line Males tion ? + $ -/+

~~

NMRI/Bom [Mta-] C57BL/6J [Mta+] C57BL/6J [Mta+] C57BL/6J [Mta+] C57BL/6J [Mta+] C57BL/6J [Mta+]

DBA/PJ [Mta'] NMRI/Bom [Mta-] NMRI/Bom [Mta-] NMRI/Bom [Mta-] NMRI/Bom [Mta-]

A.CA [Mta+] NZB/Bom [Mta-] NZB/Bom [Mta-] NZB/Bom [Mta-] NZB/Bom [Mta-] NZB/Bom [Mta-] NZB/Bom [Mta-] NZB/Bom [Mta-] NZB/Bom [Mta-] NZB/Bom [Mta-] NZB/Bom [Mta-] NZB/Bom [Mta-]

1 0 + 8 8 / 0

2 8 + 0 8 / 0

3 3 + 2 5/0

4 4 + 2 6 / 0

5 0 + 5 5/0

1 1 + 4 0/5

2 4 + 1 0/5

3 5 + 0 0/5

4 2 + 3 0/5

1 1 0 + 4 0/14

2 0 + 4 0/4

3 3 + 1 0/4

4 0 + 4 0/4

5 2 + 2 0/4

6

o + o

o/o

7 0 + 4 0/4

8 5 + 3 0 / 8

9 2 + 3 0/5

10 4 + 1 0/5

11 2 + 2 0/4

NZB/Bom [Mta-] (A.CA X NZB)F, [Mta'] 1 3

+

10 13/0

NZB/Bom [Mta-] ( A C A x NZB) x NZB7 [Mta+] 8 6 + 1 7/0

a Lists only mice typed by the killer assay. Since all female breeders must have had the same

type as their offspring, the total number sampled in each generation may be increased by at least two.

The stock from which the NZ mice were inbred must have contained both

Mta+ and Mta- mice. This stock originally came from a colony of obscure origin

maintained at Mill Hill, London, during the twenties

(BIELCHOWSKY

and

GOOD-

ALL

1970). Unfortunately, we do not know of any other descendants from that

colony. Published records show no link between NZB and NMRI mice (FESTING

1979; MORSE

1981). It will be interesting to analyze the mitochondrial DNA of

the Mta- mice.

CYTOPLASMIC INHERITANCE IN MICE

493

T killer lymphocytes. The hypothesis requires biochemical confirmation which

will have to wait until antibodies specific for Mta become available,

The Mta type of a mouse is fixed before birth, as it cannot be changed by

foster-nursing or contact with mice of another type. Recent embryo transfer

experiments show that it is transmitted in the egg and not determined by

intrauterine influences (FISCHER

LINDAHL

and BURKI 1982). Examples of maternal

inheritance in mice are rare (reviewed by GRUN

1976

and MCLAREN

1979), and

we are not aware of any with the same strain distribution as Mta. A mitochon-

drial gene or a defective virus seem the most likely extrachromosomal genetic

vectors for Mta.

We are grateful to DRS. D. BENNETT, A. GROPP, J.-L. GUENET, P. HJORTH, J. KNIGHT, W. SCHAFER,

D.

J. SCHENDEL and H. WINKING for mice and cells, and to DR. I. M ~ L L E R NIELSEN and Ms H. HOLST at G1. Bomholtgaard for the production of foster-nursed mice. We thank DRS. M. F. W. FESTING and H. C. MORSE 111 for information and Drs. S. FAZEKAS de STCROTH and C. STEINBERG for discussions and critical reading of this manuscript. The Basel Institute for Immunology was founded and is supported by F. Hoffmann-La Roche and Co. Ltd., Basel, Switzerland.

LITERATURE CITED

BIELCHOWSKY, M. and C. M. GOODALL, 1970 Origin of inbred NZ mouse strains. Cancer Res. 3 0

834-836.

ENGELS, W. R., 1979 Hybrid dysgenesis in Drosophila melanogaster: rules of inheritance of female sterility. Genet. Res. 33: 219-236.

FERRIS, S. D., R. D. SAGE, and A. C. WILSON, 1982 Evidence from mtDNA sequences that common laboratory strains of inbred mice are descended from a single female. Nature 295: 163-165. FESTING, M. F. W., 1979 Inbred Strains in Biomedical Research. MacMillan Press, London. FINNEY, D.

J.,

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