Singapore - Developmental biology: Switching to neurons

Researchers identify a genetic switch that controls differentiation of embryonic stem cells into neural cells

Embryonic stem cells (ESCs) hold great therapeutic promise due to their ability to maintain themselves through a process known as self-renewal and as they can potentially transform into any cell type in the body. The differentiation of ESCs into other cell types is a complex process involving the coordinated activity of multiple genes and signalling pathways; the exact mechanisms by which many of these pathways are regulated are still unclear.

In a development that promises to shed more light on these processes, a research team led by Leah Vardy at the A*STAR Institute of Medical Biology has identified a gene that is required to maintain ESCs in an undifferentiated state, and the activity of which is reduced when ESCs differentiate to progenitor nerve cells1.

Using microarray analytical technology, Vardy and her colleagues identified almost 200 examples of messenger RNAs (mRNAs) that are regulated at the level of protein synthesis on the differentiation of mouse ESCs into neuronal progenitor cells. Messenger RNAs are transcribed copies of gene-coding DNA sequences which are translated into proteins. Both transcription and translation can be regulated to control protein synthesis.

Further analysis revealed that one mRNA, Amd1, is regulated exclusively at the translation stage during differentiation of ESCs into neuronal progenitors. Amd1 codes for production of AMD1, an enzyme that is required for the synthesis of the polyamines spermine and spermidine, two molecules that are known to be important for growth and differentiation processes, although their precise functions in ESCs are as yet unknown. AMD1 levels are typically high in ESCs but are significantly reduced, or down-regulated, in the precursors to nerve cells.

The researchers found that regulation of Amd1 led to a decrease in production of the enzyme AMD1, with a corresponding drop in production of spermine and an altered ratio of polyamines in these cells. The team also uncovered evidence that this process is controlled by a microRNA called miR-762. In contrast, over-expression of Amd1 or addition of spermine was shown to block differentiation of ESCs into precursors to nerve cells.

Together, these results suggest that miR-762 represses Amd1 translation during differentiation of ESCs into neural progenitor cells, leading to reduced synthesis of spermine, which normally inhibits neuronal differentiation. They also demonstrate an essential role for AMD1 and the polyamines in maintaining ESC self-renewal and highlight the importance of regulation of polyamine levels for neural differentiation.

"We are now planning to further characterize the molecular targets of the polyamines in ESCs and cells undergoing directed differentiation," says Vardy.

The A*STAR-affiliated researchers contributing to this research are from the Institute of Medical Biology

References

1. Zhang, D., et al. AMD1 is essential for ESC self-renewal and is translationally down-regulated on differentiation to neural precursor cells. Genes and Development 26, 461–473 (2012). | article