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Homeobox gene Distal-Less 3 is a regulator of villous cytotrophoblast differentiation and its expression is increased in human idiopathic foetal growth restriction

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Abstract

Human idiopathic foetal growth restriction (FGR) is frequently associated with placental insufficiency. In our previous studies, we have reported the isolation and characterisation of the homeobox gene Distal-less 3 (DLX3) in the human placenta. In this study, we have investigated the level of DLX3 expression in idiopathic FGR-affected placentae and determined its functional role in villous trophoblast differentiation. FGR-affected placentae (n = 25) were collected based on well-defined clinical criteria and matched for gestation with control uncomplicated pregnancies (n = 25). Real-time polymerase chain reaction and immunoblotting showed increased DLX3 mRNA and protein expression in FGR-affected placentae compared with gestation-matched controls. Qualitative immunohistochemistry revealed DLX3 localisation in the syncytiotrophoblast, cytotrophoblasts and endothelial cells surrounding the foetal capillaries in both FGR-affected and control placentae. Down-regulation of DLX3 in primary villous trophoblast cells and a trophoblast-derived cell line showed decreased expression of differentiation markers, 3βHSD, βhCG and syncytin. Therefore, we conclude that increased DLX3 expression in FGR may contribute to trophoblast dysfunction observed in FGR.

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Acknowledgments

The authors wish to thank the consenting patients and the clinical and research midwives, Sue Nisbet and Sue Duggan, for the supply of preterm and term control placental tissues. Funding support for this work was provided from the Australian National Health and Medical Research Council (NHMRC project grant #509140) to Dr. P. Murthi, and by the postgraduate scholarship support to A. Chui from The Royal Women’s Hospital and an Arthur Nylasy Award and a Felix Meyer Postgraduate Scholarship, both from The University of Melbourne.

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Correspondence to Padma Murthi.

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Chui, A., Tay, C., Cocquebert, M. et al. Homeobox gene Distal-Less 3 is a regulator of villous cytotrophoblast differentiation and its expression is increased in human idiopathic foetal growth restriction. J Mol Med 90, 273–284 (2012). https://doi.org/10.1007/s00109-011-0836-1

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