Skip to main content

Spectrum: Autism Research News

Molecular mechanisms: Rett protein forms vary in mouse brain

by  /  27 May 2014
THIS ARTICLE IS MORE THAN FIVE YEARS OLD

This article is more than five years old. Autism research — and science in general — is constantly evolving, so older articles may contain information or theories that have been reevaluated since their original publication date.

Compare, contrast: The two forms of MeCP2 — e1 (left) and e2 (right) — are expressed differently in the olfactory bulb (top), striatum (middle) and cortex (bottom) of mice.

The protein underlying Rett syndrome exists in two different forms that differ in their distribution throughout the brain, reports a study published 3 March in PLoS One1.

The two forms are expressed at different levels in various areas of the adult mouse brain, and those levels change throughout development, the researchers found.

Another study, published 3 April in PLoS ONE2, reports that each of the so-called isoforms, e1 and e2, affects the way hundreds of genes are regulated.

The MeCP2 protein binds to and regulates many key genes involved in learning and memory. Abnormal MeCP2 levels lead to brain dysfunction. A mutation that inactivates the protein, for example, can cause Rett syndrome.

How mutations affecting the protein lead to symptoms still is not clear, because MeCP2’s downstream effects are widely varied. The existence of the two forms may explain part of this complexity. The e1 form is expressed fairly evenly throughout the brain. In contrast, e2 levels are higher in the olfactory bulb and cerebellum and lower in the brain stem than in other regions. Overall, the whole brain expresses about three times as much e1 as e2.

The researchers also tracked their expression in developing mouse fetuses. The e1 form is present in the brain midway through the 21-day gestation period. However, e2 shows up 18 days in. Both isoforms increase significantly in the first seven days after birth, a critical period for neurons to mature and form connections.

The group involved in the April study has taken steps to determine the effect of the isoforms by identifying which genes respond to increased levels of e1 and e2. High levels of e1 in human neurons leads to a more than threefold change in the expression of approximately 800 genes, and high levels of e2 to a more than threefold change in about 230 genes, they found.

The genes most affected include some involved in building connections between neurons, in regulating cardiovascular function, aiding communication between cells or speech development.

References:

1. Olson C.O. et al. PLoS ONE 9,e90645 (2014) PubMed

2. Orlic-Milacic M. et al. PLoS ONE 9, e91742 (2014) PubMed