Heterozygous deletion of Sox9 in mouse mimics the gonadal sex reversal phenotype associated with campomelic dysplasia in humans.

Autor:	Bagheri-Fam S; Department of Anatomy and Neuroscience, The University of Melbourne, Parkville, VIC 3010, Australia., Combes AN; Department of Anatomy and Neuroscience, The University of Melbourne, Parkville, VIC 3010, Australia.; Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, VIC 3052, Australia., Ling CK; Department of Anatomy and Neuroscience, The University of Melbourne, Parkville, VIC 3010, Australia., Wilhelm D; Department of Anatomy and Neuroscience, The University of Melbourne, Parkville, VIC 3010, Australia.
Jazyk:	angličtina
Zdroj:	Human molecular genetics [Hum Mol Genet] 2021 Feb 04; Vol. 29 (23), pp. 3781-3792.
DOI:	10.1093/hmg/ddaa259
Abstrakt:	Heterozygous mutations in the human SOX9 gene cause the skeletal malformation syndrome campomelic dysplasia which in 75% of 46, XY individuals is associated with male-to-female sex reversal. Although studies in homozygous Sox9 knockout mouse models confirmed that SOX9 is critical for testis development, mice heterozygous for the Sox9-null allele were reported to develop normal testes. This led to the belief that the SOX9 dosage requirement for testis differentiation is different between humans, which often require both alleles, and mice, in which one allele is sufficient. However, in prior studies, gonadal phenotypes in heterozygous Sox9 XY mice were assessed only by either gross morphology, histological staining or analyzed on a mixed genetic background. In this study, we conditionally inactivated Sox9 in somatic cells of developing gonads using the Nr5a1-Cre mouse line on a pure C57BL/6 genetic background. Section and whole-mount immunofluorescence for testicular and ovarian markers showed that XY Sox9 heterozygous gonads developed as ovotestes. Quantitative droplet digital PCR confirmed a 50% reduction of Sox9 mRNA as well as partial sex reversal shown by an upregulation of ovarian genes. Our data show that haploinsufficiency of Sox9 can perturb testis development in mice, suggesting that mice may provide a more accurate model of human disorders/differences of sex development than previously thought. (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
Databáze:	MEDLINE
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