Cellular resolution maps of X chromosome inactivation: implications for neural development, function, and disease

Hao Wu; Junjie Luo; Huimin Yu; Amir Rattner; Alisa Mo; Yanshu Wang; Philip M Smallwood; Bracha Erlanger; Sarah J Wheelan; Jeremy Nathans

doi:10.1016/j.neuron.2013.10.051

Cellular resolution maps of X chromosome inactivation: implications for neural development, function, and disease

Neuron. 2014 Jan 8;81(1):103-19. doi: 10.1016/j.neuron.2013.10.051.

Authors

Hao Wu¹, Junjie Luo², Huimin Yu³, Amir Rattner³, Alisa Mo⁴, Yanshu Wang¹, Philip M Smallwood¹, Bracha Erlanger⁵, Sarah J Wheelan⁶, Jeremy Nathans⁷

Affiliations

¹ Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
² Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
³ Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁴ Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁵ Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁶ Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Division of Biostatistics and Bioinformatics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁷ Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: [email protected].

Abstract

Female eutherian mammals use X chromosome inactivation (XCI) to epigenetically regulate gene expression from ∼4% of the genome. To quantitatively map the topography of XCI for defined cell types at single cell resolution, we have generated female mice that carry X-linked, Cre-activated, and nuclear-localized fluorescent reporters--GFP on one X chromosome and tdTomato on the other. Using these reporters in combination with different Cre drivers, we have defined the topographies of XCI mosaicism for multiple CNS cell types and of retinal vascular dysfunction in a model of Norrie disease. Depending on cell type, fluctuations in the XCI mosaic are observed over a wide range of spatial scales, from neighboring cells to left versus right sides of the body. These data imply a major role for XCI in generating female-specific, genetically directed, stochastic diversity in eutherian mammals on spatial scales that would be predicted to affect CNS function within and between individuals.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Animals, Newborn
Brain / cytology
Brain / embryology
Brain / growth & development
Choline O-Acetyltransferase / metabolism
Embryo, Mammalian
Female
Functional Laterality / genetics
Gene Expression Regulation, Developmental / genetics
Green Fluorescent Proteins / genetics
Humans
Hypoxanthine Phosphoribosyltransferase / genetics
Mice
Mice, Transgenic
Mosaicism*
Nerve Tissue Proteins / metabolism*
Neurons / classification
Neurons / metabolism*
Polymorphism, Single Nucleotide / genetics
Retina / cytology
X Chromosome / genetics*
X Chromosome Inactivation / genetics*

Substances

Nerve Tissue Proteins
Green Fluorescent Proteins
Choline O-Acetyltransferase
Hypoxanthine Phosphoribosyltransferase

Abstract

Publication types

MeSH terms

Substances

Grants and funding