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Hum. Reprod. Advance Access originally published online on June 11, 2007
Human Reproduction 2007 22(8):2232-2242; doi:10.1093/humrep/dem136
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© The Author 2007. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Reprogramming following somatic cell nuclear transfer in primates is dependent upon nuclear remodeling

S.M. Mitalipov1,5, Q. Zhou2, J.A. Byrne1, W.Z. Ji3, R.B. Norgren4 and D.P. Wolf1

1 Division of Reproductive Sciences, Oregon National Primate Research Center, Oregon Health and Science University, 505 NW 185th Avenue, Beaverton, OR 97006, USA 2 Institute of Zoology, Chinese Academy of Sciences, Beijing, China 3 Kunming Institute of Zoology, Kunming Primate Research Center, Chinese Academy of Sciences, Kunming, Yunnan, China 4 Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, NE, USA

5 Correspondence address. Tel: +1-503-614-3709; Fax: +1-503-533-2494; E-mail: mitalipo{at}ohsu.edu

BACKGROUND: Somatic cell nuclear transfer (SCNT) requires cytoplast-mediated reprogramming of the donor nucleus. Cytoplast factors such as maturation promoting factor are implicated based on their involvement in nuclear envelope breakdown (NEBD) and premature chromosome condensation (PCC). Given prior difficulties in SCNT in primates using conventional protocols, we hypothesized that the ability of cytoplasts to induce nuclear remodeling was instrumental in efficient reprogramming.

METHODS: NEBD and PCC in monkey (Macaca mulatta) SCNT embryos were monitored by lamin A/C immunolabeling.

RESULTS: Initially, a persistent lamin A/C signal from donor cell nuclei after fusion with cytoplasts was observed indicative of incomplete NEBD following SCNT and predictive of developmental arrest. We then identified fluorochrome-assisted enucleation and donor cell electrofusion as likely candidates for inducing premature cytoplast activation and a consequent lack of nuclear remodeling. Modified protocols designed to prevent premature cytoplast activation during SCNT showed robust NEBD and PCC. Coincidently, over 20% of SCNT embryos reconstructed with fetal fibroblasts progressed to blastocysts. Similar results were obtained with other somatic cells. Reconstructed blastocysts displayed patterns of Oct-4 expression similar to fertilized embryos reflecting successful reprogramming.

CONCLUSIONS: Our results represent a significant breakthrough in elucidating the role of nuclear remodeling events in reprogramming following SCNT.

Key words: somatic cell nuclear transfer/nuclear remodeling/premature cytoplast activation/lamin A/C/primate

Submitted on December 26, 2006; resubmitted on February 20, 2007; accepted on April 17, 2007.


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