With the emergence of sex-determination by sex chromosomes, which differ in composition and number between males and females, appeared the need to equalize X-chromosomal gene dosage between the sexes. Mammals have devised the strategy of X-chromosome inactivation (XCI), in which one of the two X-chromosomes is rendered transcriptionally silent in females. In the mouse, the best-studied model organism with respect to XCI, this inactivation process occurs in different forms, imprinted and random, interspersed by periods of X-chromosome reactivation (XCR), which is needed to switch between the different modes of XCI. In this review, I describe the recent advances with respect to the developmental control of XCI and XCR and in particular their link to differentiation and pluripotency. Furthermore, I review the mechanisms, which influence the timing and choice, with which one of the two X-chromosomes is chosen for inactivation during random XCI. This has an impact on how females are mosaics with regard to which X-chromosome is active in different cells, which has implications on the severity of diseases caused by X-linked mutations.

The work was supported by the Spanish Ministry of Economy and Competitiveness,'Centro de Excelencia Severo Ochoa 2013–2017', SEV-2012-0208 and for a Plan Estatal Grant to B.P. (BFU2014-55275-P)