Thornhill, Alan Russell; (1996) Effects of the sex chromosomes on early growth and development in the mouse. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Mice with normal and aneuploid sex chromosome complements are used to investigate the role of the sex chromosomes in mammalian growth and rate of development. Early developmental differences between the sexes are observed in a number of mammalian species. In mice, males from the CD1 strain form a blastocoel earlier than females from the same clutch (Tsunoda et al, 1985). This developmental advantage translates to a significant cell number difference at 3.5 dpc and segregates with the Y-chromosome (Burgoyne, 1993). In Chapter 5, fluorescent in-situ hybridisation (FISH) is used to sex interphase blastomeres and blastocyst cell numbers are determined, serving to replicate Burgoyne's (1993) findings and validate the approach. Information is also provided for other Y-chromosomes of interest. A male developmental advantage over females has also been documented for postimplantation stages (Seller and Perkins-Cole, 1987). Experiments in Chapter 3, and more extensive data elsewhere (Burgoyne et al., 1995), have shown that the Y-linked effect observed at the preimplantation blastocyst stage is not of primary significance during the postimplantation period. In fact, the developmental delay of XX relative to XY fetuses is due, primarily, to the difference in X-chromosome constitution. One component of the difference in X-chromosome constitution, parental origin, is investigated in Chapter 2. XO fetuses carrying a paternal X-chromosome are significantly smaller than XMO fetuses and it is concluded that an X-chromosome imprint affects postimplantation growth and development. In an attempt to assess the relative effects of the imprinted maternal and paternal X in the etiology of XX-XY differences. Chapter 6 describes the consequences of manipulating the relative expression of the maternal and paternal X-chromosomes using combinations of Xce alleles. The combination of Xce alleles inherited clearly influences the size of the XX-XY difference by means of two opposing effects. It is proposed that fetal size is influenced by an early preimplantation positive maternal effect (the consequence of egg derived X-linked gene products) and a later negative or retarding effect which occurs in the XX embryo as a result of over-expression of X-linked genes just prior to X-inactivation. Humans with abnormal numbers of sex chromosomes often show significant postnatal growth differences when compared with controls. XO women are growth retarded, while XXY and XYY men are taller than average. Preliminary data from 'XXY' and 'XYY' mice (Chapter 7) suggest that an extra Y-chromosome does not influence postnatal weight gain, contrary to the expectations from Chapter 4 in which a postimplantation developmental advantage is observed for 'XXY' fetuses. XPO mice (born to 'XX' mothers) gain weight more slowly than XX controls in the pre-weaning period (Burgoyne et al., 1983a). Preliminary data in Chapter 7 indicate that the postnatal weight gain of both XPO and XMO mice is similarly reduced and suggest that, rather than an imprinting effect, the growth deficit is the consequence of a single dose of an X-linked gene which escapes inactivation. Thus, the XO mouse may prove to be a useful model for some aspects of the growth retardation observed in human X-monosomy.

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