Dr Zhang and others go on to show that high levels of Amd1 are essential for the maintenance of ES cells. Reduction of Amd1 levels in ES cells caused the cells to lose their ability to self renew and they started to differentiate. They also demonstrate that increasing the levels of Amd1 enabled the cells to remain in an ES cell like state even in conditions that normally promote differentiation. The authors link these observations to the polyamines and suggest that tight regulation of the levels of polyamines is essential to maintain cells in an ES cell like state.

Their work and the work of others also implicate the polyamines as being critical for efficient differentiation to certain lineages. They show that spermine blocks NPC differentiation and other groups have shown that the presence of spermine at specific time windows can enhance the differentiation of ES cells to muscle cells. While many of the molecular targets of the polyamines are not known it is becoming increasingly clear that they play a major role in the regulation of ES cell differentiation. By understanding how these polyamines function in different cells during the differentiation process the hope is that they can be manipulated to enhance the efficiency of differentiation.

Regulation of gene expression during ES cell differentiation is complex, and there is extensive cross talk between the different layers of control. There is now a greater need to understand the finer levels of control that lie at the post-transcriptional level. The polyamine pathway is a fine example of this complex regulation, as the enzymes within the pathway, in addition to being transcriptionally regulated, are under heavy translational control as well to ensure each of the polyamines are present at the appropriate levels. These polyamines themselves serve to further regulate gene expression.

Understanding the full picture of gene expression control will involve its interrogation at all levels to identify both the regulated genes and mRNAs and the regulators themselves. As this network of controls becomes more defined so too will our ability to direct the differentiation of ES cells taking us one step further to realizing their clinical potential.
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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 Dev; 2012. 26(5): p. 461-73.

2. Igarashi, K and K Kashiwagi; 'Modulation of cellular function by polyamines'; Int J Biochem Cell Biol; 2010. 42(1): p. 39-51.

3. Sasaki, T, H Matsuoka, and M Saito; 'Generation of a multi-layer muscle fiber sheet from mouse ES cells by the spermine action at specific timing and concentration'; Differentiation; 2008. 76(10): p. 1023-30.