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Pregnancy Timeline by SemestersFetal liver is producing blood cellsHead may position into pelvisBrain convolutions beginFull TermWhite fat begins to be madeWhite fat begins to be madeHead may position into pelvisImmune system beginningImmune system beginningPeriod of rapid brain growthBrain convolutions beginLungs begin to produce surfactantSensory brain waves begin to activateSensory brain waves begin to activateInner Ear Bones HardenBone marrow starts making blood cellsBone marrow starts making blood cellsBrown fat surrounds lymphatic systemFetal sexual organs visibleFinger and toe prints appearFinger and toe prints appearHeartbeat can be detectedHeartbeat can be detectedBasic Brain Structure in PlaceThe Appearance of SomitesFirst Detectable Brain WavesA Four Chambered HeartBeginning Cerebral HemispheresFemale Reproductive SystemEnd of Embryonic PeriodEnd of Embryonic PeriodFirst Thin Layer of Skin AppearsThird TrimesterSecond TrimesterFirst TrimesterFertilizationDevelopmental Timeline
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Home | Pregnancy Timeline | News Alerts |News Archive Jan 10, 2014

 

"Calico cats have mottled coat colors and are only female. They have two different versions of a gene for coat color located on their X chromosomes: one version from their mother and the other from their father.

"Their fur is orange or black depending on which X chromosome is silenced in a particular patch of cells."

Jeremy Nathans, M.D., Ph.D.








Patterns of X chromosome silencing in cells of the cornea, skin, cartilage and inner ear of mice.
The X chromosomes from the mother and father are differentially labeled green and red,
respectively. Cells that silence the maternal X chromosome appear red;
those that silence the paternal X chromosome appear green.

Image Credit: Nathans lab, courtesy of Neuron

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Color reveals which X chromosome "off" in girls

Johns Hopkins researchers have color-coded many different tissues in female mice to display which of their two X chromosomes is inactive, or "silenced."

Scientists have long known that the silencing of one X chromosome in females — women have two X chromosomes in every cell — is a normal occurrence. The consequences can be significant though, if one X chromosome carries a normal copy of a gene and the other X chromosome carries a mutated copy.

By genetically tagging different X chromosomes with genes that code for red or green fluorescent proteins, scientists say they can now peer into different tissue types and analyze genetic diversity within and between individual females.

Published on Jan. 8 in the journal Neuron, a summary of the research shows wide-ranging variation in patterns of so-called X chromosome inactivation within tissues, on the left or right sides of a centrally located tissue (like the brain), among different tissue types, between paired organs (like the eyes) and amongst individuals.


"Calico cats have mottled coat colors, and are only female. They have two different versions of a gene for coat color located on their X chromosomes: one version from their mother and the other from their father.

"Their fur is orange or black depending on which X chromosome is silenced in a particular patch of skin cells.

"X chromosome inactivation actually occurs in all cells in female mammals, including humans, affecting most of the X chromosome genes. Although this phenomenon has been known for over 50 years, it could not be clearly visualized in internal organs and tissues until this protein tagging procedure was developed."

Jeremy Nathans, M.D., Ph.D., professor of molecular biology and genetics, Johns Hopkins University and a Howard Hughes Medical Institute investigator


Nathans adds that early in the development of most mammals, when a female embryo has only about 1,000 cells, each cell makes a "decision" to inactivate one of the two X chromosomes, a process that silences most of the genes on that chromosome. The choice of which X chromosome to inactivate appears to be random, but when those cells divide, their descendants maintain that initial decision.


In the new research, the Johns Hopkins team mated female mice carrying two copies of the gene for green fluorescent protein — one on each of the two X chromosomes — with male mice whose single X chromosome carried the gene for a red fluorescent protein. The female offspring from this mating had cells that glowed red or green based on which X chromosome was silenced.

Additionally, the team engineered the mice so not all of their cells were color-coded, to make it easier to distinguish one cell from another. Their system allowed only a single cell type in each mouse, such as heart muscle cells, to be color-coded. This genetic trick resulted in red and green color maps in distinctive patterns for each cell and tissue type tagged.


Nathans explains that the color patterns are determined by the way each tissue develops: some tissues are created from a very small number of "founder cells" in the early embryo; others are created from a large number of "founder cells." Statistically, the larger the group of founder cells, the greater the chance of having a nearly equal number of red and green cells tagged.


Although the ratio of founding cells is roughly preserved as tissue grows, distribution of these cells is determined by how much movement occurs during development of that tissue type.

For example, blood cells move a lot, so the red and green cells become very intermingled. In contrast, skin cells move very little, each patch of skin descendant from a single cell sharing the same inactive X chromosome — therefore of the same color — and create a coarse patchwork of red and green.


Normally, the pattern of X chromosome inactivation is not easily seen. Nathans  feels his color-coding technique is likely to be valuable for many studies, especially in research on variations caused by changes in DNA sequence on the X chromosome — X-linked gene variations. Hemophilia and color blindness, are X-linked gene variations and relatively common, partly because the X chromosome carries so many genes — approximately 1,000, or close to 4 percent of the total genome.


Males who inherit an X-linked disease usually suffer its effects because they have no second X chromosome to compensate for the mutant version of the gene.

Female relatives, on the other hand, are more typically "carriers" of X-linked diseases. They have the ability to pass the disease along to their male children, but do not suffer from it themselves due to compensation by the normal copy of that gene on their second X chromosome.


In certain female carriers, however, cells with an X chromosome silenced by a mutated gene cannot be compensated for by the X chromosome with a normal gene.

Nathans and his team saw a pattern when they examined retinas of mice carriers for mutations in the Norrie disease gene, located on the X chromosome. The Norrie disease gene codes for Norrin protein, which controls blood vessel formation in the retina. Women who are carriers for Norrie disease can have defects in their own retinas, with some women more affected than others. Sometimes one eye is more affected than the other eye in the same individual.

The team found in Norrie disease carrying female mice, variation in blood vessel structure corresponding to localized variations in inactivation on  their X chromosome. When the X chromosome with a normal copy of the Norrie disease gene is silenced, blood vessels nearby fail to form properly. In contrast, when the X chromosome carrying the mutated copy of the Norrie disease gene was silenced (turned off), nearby blood vessels did develop normally.

"X chromosome inactivation is a fascinating aspect of mammalian biology," says Nathans. "This new technique for visualizing the pattern of X chromosome inactivation should be particularly useful for looking at brain development. Including how X inactivation contributes to differences between left and right sides of female brain development, differences between males and females brain structure, and between females — including identical twins."

Highlights
X-linked, dual color, Cre-activated reporters were used to visualize X-inactivation
Cellular resolution maps of X-inactivation were generated for various CNS cell types
Variation in X-inactivation determines phenotype in a mouse model of Norrie disease
RNA-seq reveals genes that obey or escape X-inactivation in the developing brain

Summary
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.

Other authors of the report include Hao Wu, Junjie Luo, Huimin Yu, Amir Rattner, Alisa Mo, Yanshu Wang, Philip Smallwood, Bracha Erlanger and Sarah Wheelan of the Johns Hopkins University School of Medicine.

Neuron, Volume 81, Issue 1, 103-119, 8 January 2014
Copyright © 2014 Elsevier Inc. All rights reserved.
10.1016/j.neuron.2013.10.051

This work was supported by grants from the National Cancer Institute (P30 CA006973), the Human Frontier Science Program, the Howard Hughes Medical Institute and Johns Hopkins' Brain Science Institute.