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PMID: 11106380 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Maternal germ-line transmission of mutant mtDNAs from embryonic stem cell-derived chimeric mice.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 97 ·No. 26 ·2000-12-19 ·Pages 14461-6

Sligh JE, Levy SE, Waymire KG, Allard P, Dillehay DL, Nusinowitz S, Heckenlively JR, MacGregor GR, Wallace DC

Abstract

We report a method for introducing mtDNA mutations into the mouse female germ line by means of embryonic stem (ES) cell cybrids. Mitochondria were recovered from the brain of a NZB mouse by fusion of synaptosomes to a mtDNA-deficient (rho degrees ) cell line. These cybrids were enucleated and the cytoplasts were electrofused to rhodamine-6G (R-6G)-treated female ES cells. The resulting ES cell cybrids permitted transmission of the NZB mtDNAs through the mouse maternal lineage for three generations. Similarly, mtDNAs from a partially respiratory-deficient chloramphenicol-resistant (CAP(R)) cell line also were introduced into female chimeric mice and were transmitted to the progeny. CAP(R) chimeric mice developed a variety of ocular abnormalities, including congenital cataracts, decreased retinal function, and hamaratomas of the optic nerve. The germ-line transmission of the CAP(R) mutation resulted in animals with growth retardation, myopathy, dilated cardiomyopathy, and perinatal or in utero lethality. Skeletal and heart muscle mitochondria of the CAP(R) mice were enlarged and atypical with inclusions. This mouse ES cell-cybrid approach now provides the means to generate a wide variety of mouse models of mitochondrial disease.

MeSH Terms
Animals Brain/pathology Cell Line Chimera Chloramphenicol/pharmacology DNA, Mitochondrial Drug Resistance Female Genomic Imprinting Male Mice Mice, Inbred C57BL Mice, Transgenic Mutation Myocardium/pathology Ovum Pedigree Phenotype Retinal Cone Photoreceptor Cells/pathology Retinal Rod Photoreceptor Cells/pathology Stem Cells
Chemicals
DNA, Mitochondrial Chloramphenicol
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Sligh J E
Center for Molecular Medicine, Departments of Dermatology and Pathology and Division of Animal Resources, Emory University School of Medicine, 1462 Clifton Road, Atlanta, GA 30322, USA.
Levy S E
Waymire K G
Allard P
Dillehay D L
Nusinowitz S
Heckenlively J R
MacGregor G R
Wallace D C
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.250491597
Published
2000-12-19
Pages
14461-6
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC18941
Subset
IM
Grants
NHLBI NIH HHS · HL45572 · United States
NINDS NIH HHS · R01 NS21328 · United States
NINDS NIH HHS · R01 NS021328 · United States
NIA NIH HHS · R01 AG013154 · United States
NIA NIH HHS · AG13154 · United States
Corrections
CommentIn
PMID: 11209045
External Links
PubMed source DOI: 10.1073/pnas.250491597 PMC Full Text View journal details
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