The X-linked Xist gene encodes a large untranslated RNA that has been implicated in mammalian dosage compensation and in spermatogenesis. To investigate the function of the Xist gene product, we have generated male and female mice that carry a deletion in the structural gene but maintain a functional Xist promoter. Mutant males were healthy and fertile. Females that inherited the mutation from their mothers were also normal and had the wild-type paternal X chromosome inactive in every cell. In contrast to maternal transmission, females that carry the mutation on the paternal X chromosome were severely growth-retarded and died early in embryogenesis. The wild-type maternal X chromosome was inactive in every cell of the growth-retarded embryo proper, whereas both X chromosomes were expressed in the mutant female trophoblast where X inactivation is imprinted. However, an XO mouse with a paternally inherited Xist mutation was healthy and appeared normal. The imprinted lethal phenotype of the mutant females is therefore due to the inability of extraembryonic tissue with two active X chromosomes to sustain the embryo. Our results indicate that the Xist RNA is required for female dosage compensation but plays no role in spermatogenesis.

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Xist-deficient mice are defective in dosage compensation but not spermatogenesis.

The Coat Colors of Mice

Summary

1. The review considers information from mammalian embryology relevant to X-chromosome inactivation, and from X-inactivation relevant to mammalian embryology.



2. Properties of the inactive-X, by which it may be recognized are: sex chromatin, heteropycnosis, late replication and the absence of gene product. Each of these has advantages and disadvantages in particular circumstances. In some species the X carries constitutive heterochromatin, which must be distinguished from the facultative region.



3. The time of X-chromosome inactivation can be estimated from the time of appearance of sex chromatin or late replication, or inferred from the appearance of heterozygotes for X-linked genes or of experimental chimaeras. The estimated time varies with species, and in the mouse and rabbit is near the time of increase in RNA synthesis.



4. Whereas in eutherian mammals either the maternally or the paternally derived X may be inactivated in different cell lines, in marsupials the paternal X is always the inactive one.



5. During development various factors act to distort the patterns produced by random X-inactivation. These factors include cell selection, transfer of gene product, and migration and mingling of cells.



6. There is no clear evidence that X-chromosome inactivation is not complete.



7. In female germ cells both X-chromosomes appear to be active. In male ones both X and Y appear inactive during most of spermatogenesis, although probably in early stages all X chromosomes present are active.



8. The active and inactive X-chromosomes may be differentiated by presence or absence of some non-histone protein or other polyanionic substance.



9. If the genes concerned in synthesis or attachment of this substance are on the X-chromosome then the differentiation will be self-maintaining.



10. The initiation of the differentiation requires either the attachment of different X-chromosomes to different sites, or some interaction of X-linked and autosomal genes, concerned in inducing or repressing activity. Some possible models are discussed.

X-chromosome inactivation and developmental patterns in mammals

Targeted Mutagenesis of Tsix Leads to Nonrandom X Inactivation

The effect of chromosomal position on the expression of the drosophila xanthine dehydrogenase gene

Publisher Summary This chapter reviews that the use of data from the X-A translocations in the mouse allowed hypothetical answers to be formulated regarding the selection of one active X chromosome, physical linkage of autosomal genes to the active or inactive X chromosomal material regarding inactivation or activation, complete inactivation of an intact X chromosome versus incomplete inactivation of the X portion of an X-A segment, and random versus nonrandom inactivation with respect to primary and secondary causes. The chapter also discusses an interesting model for a gene regulation control system, which is proposed in higher organisms. The inactivation of the X chromosome would indicate that there are hierarchies of gene regulation. The X chromosome would be expected to have all the control systems. This latter system is hypothesized to be the determination mechanism for which X chromosome will be the inactive X chromosome.

X-Autosome Translocations in The Mouse: Total Inactivation Versus Partial Inactivation Of The X Chromosome

https://www.genetics.org/content/genetics/64/3-4/495.full.pdf

THE POSITION OF ru-2 AND qv WITH RESPECT TO THE FLECKED TRANSLOCATION IN THE MOUSE

A I cm3 sample of tubules from testes is placed in 5 ml of 0.7% Na-citrate for 20-30 min, then 5 ml of glacial acetic acid is added, mixed well, and allowed to stand for 30 min. The mixture is centrifuged, the supernatant removed, and 3 ml of 3 M gluconic acid is mixed with the tissue and allowed to act for 3 hr. The gluconic acid is removed with a pipette and the tissue is suspended in 5 ml of a freshly made 1:1 absolute ethanol-glacial acetic acid mixture. The tissue is drawn into and discharged from a syringe several times through an 18, a 20, and finally a 22 gauge needle to separate and suspend the cells. The cells are centrifuged and resuspended several times in fresh fixative to remove the gluconic acid. Finally, the cells are suspended in sufficient fixative to give a smear of suitable density, and air-dried preparations are made, or the suspension may be stored at 0-5 C for several days. The cells can be stained by any of the usual stains for chromosomes. This technique results in the improved sp...

Eva M. Eicher

Papers

X-Autosome Translocations in The Mouse: Total Inactivation Versus Partial Inactivation Of The X Chromosome

THE POSITION OF ru-2 AND qv WITH RESPECT TO THE FLECKED TRANSLOCATION IN THE MOUSE

An air-drying procedure for mammalian male meiotic chromosomes, following softening in gluconic acid and cell separation by an ethanol-acetic mixture.

Ernst W. Caspari: geneticist, teacher, and mentor.