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Research article - Peer-reviewed, 2022

Hmga2 deficiency is associated with allometric growth retardation, infertility, and behavioral abnormalities in mice

Lee, Mi Ok; Li, Jingyi; Davis, Brian W.; Upadhyay, Srijana; Al Muhisen, Hadil M.; Suva, Larry J.; Clement, Tracy M.; Andersson, Leif


The high mobility group AT-hook 2 (HMGA2) protein works as an architectural regulator by binding AT-rich DNA sequences to induce conformational changes affecting transcription. Genomic deletions disrupting HMGA2 coding sequences and flanking noncoding sequences cause dwarfism in mice and rabbits. Here, CRISPR/Cas9 was used in mice to generate an Hmga2 null allele that specifically disrupts only the coding sequence. The loss of one or both alleles of Hmga2 resulted in reduced body size of 20% and 60%, respectively, compared to wild-type littermates as well as an allometric reduction in skull length in Hmga2(-/-) mice. Both male and female Hmga2(-/-) mice are infertile, whereas Hmga2(+/-) mice are fertile. Examination of reproductive tissues of Hmga2(-/-) males revealed a significantly reduced size of testis, epididymis, and seminal vesicle compared to controls, and 70% of knock-out males showed externalized penis, but no cryptorchidism was observed. Sperm analyses revealed severe oligospermia in mutant males and slightly decreased sperm viability, increased DNA damage but normal sperm chromatin compaction. Testis histology surprisingly revealed a normal seminiferous epithelium, despite the significant reduction in testis size. In addition, Hmga2(-/-) mice showed a significantly reduced exploratory behavior. In summary, the phenotypic effects in mouse using targeted mutagenesis confirmed that Hmga2 is affecting prenatal and postnatal growth regulation, male reproductive tissue development, and presents the first indication that Hmga2 function is required for normal mouse behavior. No specific effect, despite an allometric reduction, on craniofacial development was noted in contrast to previous reports of an altered craniofacial development in mice and rabbits carrying deletions of both coding and noncoding sequences at the 5 ' part of Hmga2.


high mobility group AT-hook 2; CRISPR; Cas9; sterility; behavior

Published in

2022, volume: 12, number: 2, article number: jkab417

Authors' information

Lee, Mi Ok
Texas AandM University College Station
Li, Jingyi
Texas AandM University College Station
Davis, Brian W.
Texas AandM University College Station
Upadhyay, Srijana
Texas AandM University College Station
Al Muhisen, Hadil M.
Texas AandM University College Station
Suva, Larry J.
Texas AandM University College Station
Clement, Tracy M.
Texas AandM University College Station
Texas AandM University College Station
Andersson, Leif
Uppsala University
Andersson, Leif
Swedish University of Agricultural Sciences, Department of Animal Breeding and Genetics

UKÄ Subject classification

Developmental Biology

Publication Identifiers


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