Cloned lambs—lessons from pathology

Rhind, Susan; King, Tim; Harkness, Linda; Bellamy, Chris; Wallace, William; DeSousa, Paul; Wilmut, Ian

doi:10.1038/nbt0703-744

Cited by 61 publications

(37 citation statements)

References 16 publications

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“…Early gestational losses of NTembryos are often associated with aberrant placental development in livestock and mice (Hill et al 2000, De Sousa et al 2001, Ogura et al 2002. Anomalies in foetal and perinatal stage cloned calves and lambs are heterogeneous, including excessive birth weight (large offspring syndrome), defects in the gastrointestinal, cardiopulmonary, hepatic and renal systems as well as skeletal malformations (Wells et al 1997, Zakhartchenko et al 1999, Lanza et al 2001, Gibbons et al 2002, Pace et al 2002, Rhind et al 2003. Furthermore, survival beyond term is also affected with annual mortalities of 8% reported in cattle (Wells et al 2004) and early death in mice .…”

Section: Introductionmentioning

confidence: 99%

Gene expression profiling of individual bovine nuclear transfer blastocysts

Somers¹,

Smith²,

Donnison³

et al. 2006

Reproduction

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During somatic cell nuclear transfer the gene expression profile of the donor cell has to be changed or reprogrammed extensively to reflect that of a normal embryo. In this study we focused on the switching on of embryonic genes by screening with a microarray consisting of 5000 independent cDNA isolates derived from a bovine blastocyst library which we constructed for this purpose. Expression profiling was performed using linearly amplified RNA from individual day 7 nuclear transfer (NT) and genetically half-identical in vitro produced (IVP) blastocysts. We identified 92 genes expressed at lower levels in NT embryos whereas transcripts of 43 genes were more abundant in NT embryos (P % 0.05, R 1.5-fold change). A range of functional categories was represented among the identified genes, with a preponderance of constitutively expressed genes required for the maintenance of basal cellular function. Using a stringent quantitative SYBR-green real time RT-PCR based approach we found, when comparing the means of the expression levels of a larger set of individual embryos, that differences were small (! 2-fold) and only significant for two of the seven analysed genes (KRT18, SLC16A1). Notably, examination of transcript levels of a single gene in individual embryos could not distinguish an NT from a control embryo. This unpredictability of individual gene expression on a global background of multiple gene expression changes argues for a predominantly stochastic nature of reprogramming errors.

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Section: Introductionmentioning

confidence: 99%

Gene expression profiling of individual bovine nuclear transfer blastocysts

Somers¹,

Smith²,

Donnison³

et al. 2006

Reproduction

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“…D'un autre côté, il est connu que des anomalies de méthylation de l'ADN au niveau de certains îlots CpG peuvent affecter l'expression de gènes soumis à empreinte [50]. Or, de telles anomalies se retrouvent chez les clones murins [42,51], et une partie des phénotypes anormaux observés pré-sentent de fortes similarités avec ceux attribués aux défauts d'empreinte [52,53]. De tels défauts d'empreinte peuvent aussi résulter directement des conditions de manipulation des embryons (et notamment des conditions de culture [54]), mais les pertes au cours du développement sont généralement moins importantes.…”

Section: Reprogrammation à L'échelle Du Génome Ou Reprogrammation De unclassified

Reprogrammationet épigenèse

et al. 2005

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“…These abnormalities include a wide range of symptoms, such as extended gestation length, oversized offspring, aberrant placental development, cardiovasculatory and respiratory problems, immunological deficiencies, problems with tendons, adult obesity, kidney and hepatic malfunctions, behavioural changes, and a higher susceptibility to neonatal diseases. These are all commonly described as the 'large offspring syndrome' (LOS; Renard et al 1999, Tamashiro et al 2000, Ogonuki et al 2002, Perry & Wakayama 2002, Rhind et al 2003. These pathologies have most often reported in SCNT cloning of cattle, sheep and mice.…”

Section: Epigenetic Reprogramming By Scntmentioning

confidence: 99%

Epigenetic reprogramming in embryonic and foetal development upon somatic cell nuclear transfer cloning

Niemann¹,

Tian²,

King³

et al. 2008

Reproduction

196

116

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The birth of 'Dolly', the first mammal cloned from an adult donor cell, has sparked a flurry of research activities to improve cloning technology and to understand the underlying mechanism of epigenetic reprogramming of the transferred somatic cell nucleus. Especially in ruminants, somatic cell nuclear transfer (SCNT) is frequently associated with pathological changes in the foetal and placental phenotype and has significant consequences for development both before and after birth. The most critical factor is epigenetic reprogramming of the transferred somatic cell nucleus from its differentiated status into the totipotent state of the early embryo. This involves an erasure of the gene expression program of the respective donor cell and the establishment of the well-orchestrated sequence of expression of an estimated number of 10 000-12 000 genes regulating embryonic and foetal development. The following article reviews the present knowledge on the epigenetic reprogramming of the transferred somatic cell nucleus, with emphasis on DNA methylation, imprinting, X-chromosome inactivation and telomere length restoration in bovine development. Additionally, we briefly discuss other approaches towards epigenetic nuclear reprogramming, including the fusion of somatic and embryonic stem cells and the overexpression of genes crucial in the formation and maintenance of the pluripotent status. Improvements in our understanding of this dramatic epigenetic reprogramming event will be instrumental in realising the great potential of SCNT for basic biological research and for various agricultural and biomedical applications.

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Cloned lambs—lessons from pathology

Cited by 61 publications

References 16 publications

Gene expression profiling of individual bovine nuclear transfer blastocysts

Gene expression profiling of individual bovine nuclear transfer blastocysts

Reprogrammationet épigenèse

Epigenetic reprogramming in embryonic and foetal development upon somatic cell nuclear transfer cloning

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