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Xlr3b is a new imprinted candidate for X-linked parent-of-origin effects on cognitive function in mice


Imprinted genes show differential expression between maternal and paternal alleles as a consequence of epigenetic modification that can result in 'parent-of-origin' effects on phenotypic traits1. There is increasing evidence from mouse and human studies that imprinted genes may influence behavior and cognitive functioning2. Previous work in girls with Turner syndrome (45,XO) has suggested that there are X-linked parent-of-origin effects on brain development3 and cognitive functioning4, although the interpretation of these data in terms of imprinted gene effects has been questioned5. We used a 39,XO mouse model to examine the influence of the parental origin of the X chromosome on cognitive behaviors and expression of X-linked genes in brain. Our findings confirm the existence of X-linked imprinted effects on cognitive processes and identify a new maternally expressed imprinted gene candidate on the X chromosome, Xlr3b, which may be of importance in mediating the behavioral effects.

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Figure 1: Specific X-linked POEs on performance in the serial reversal learning task.
Figure 2: Microarray comparison of whole brains of 13.5-d.p.c. 39,XpO and 39,XmO embryos and verification of the genes represented by Affymetrix tag 101883_s_at as being differentially expressed.
Figure 3: Xlr3b is the only parent-of-origin–specific differentially expressed Xlr3 paralog in the MF1 mouse brain.
Figure 4: Xlr3b is imprinted and is expressed in a sexually dimorphic manner in the brain.

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We thank W. Reik and G. Kelsey for comments; S. Andrews and J. Coadwell for bioinformatic analyses; S. Mahadevaiah for help with karyotyping; S. Macleod, J. Turner and M. Szot for embryo dissections; and W. Shi and R. Fundele for reciprocal cross RNAs. The work was supported by the Biotechnology and Biological Sciences Research Council, UK and a BI Synergy Initiative (Biotechnology and Biological Sciences Research Council, UK). W.D. was sponsored by a Biotechnology and Biological Sciences Research Council Animal Science Committee studentship and was a recipient of the Oon Khye Beng Ch'hia Tsio prize studentship for Preventative Medicine (Downing College, Cambridge, UK). L.W. is a member of the Medical Research Council (UK) Co-Operative on Imprinting in Health and Disease.

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Correspondence to Lawrence Wilkinson.

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Supplementary information

Supplementary Fig. 1

Differential expression of the Xlr3 paralogues between 39,XpO and 39,XmO mice in brain is not due to residual differential blood expression. (PDF 91 kb)

Supplementary Fig. 2

Temporal/spatial properties of Xlr3 parent-of-origin specific differential expression. (PDF 94 kb)

Supplementary Fig. 3

Examination of genes adjacent to the Xlr3 cluster for parent-of-origin specific differential expression. (PDF 94 kb)

Supplementary Table 1

Behavioral comparisons of 40,XX, 39,XpO and 39,XmO mice. (PDF 105 kb)

Supplementary Table 2

Comparison of 40,XX, 40,XPafX and 40,XXPaf mice on the reversal learning task. (PDF 92 kb)

Supplementary Table 3

Primer and probe sequences. (PDF 97 kb)

Supplementary Methods (PDF 186 kb)

Supplementary Note (PDF 197 kb)

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Davies, W., Isles, A., Smith, R. et al. Xlr3b is a new imprinted candidate for X-linked parent-of-origin effects on cognitive function in mice. Nat Genet 37, 625–629 (2005).

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