Updated on 28 September 2012
Control of translation allows protein synthesis to be finely regulated both spatially and temporally at critical developmental time points. RNA binding proteins and microRNAs are the major regulators of mRNA translation. microRNAs are small non-coding RNA molecules that target mRNAs for repression. Originally identified in worms, they are now recognized as essential regulators of a wide array of cellular processes in mammalian cells. They target specific mRNAs through base pairing to complimentary sequences in the target mRNA.
Over 1,000 microRNAs are believed to exist in the human genome and each has the potential to regulate hundreds of mRNAs. They have been shown to be major players in lineage specific differentiation of ES cells, and there are numerous examples where individual miRNAs have been shown to be key regulators of differentiation decisions. ES cells that lack the core machinery to process microRNAs are rendered unable to differentiate into most lineages highlighting the essential role of these small RNAs in ES cell differentiation.
A recent study from the Institute of Medical Biology set out to identify mRNAs that are controlled at the level of translation on differentiation of mouse ES cells to early neural cells called Neural Precursor Cells (NPCs) . They identified over 100 mRNAs that are regulated at the level of protein production during differentiation. In addition they found over 20 microRNAs whose levels change dramatically on differentiation.
One protein they identified, Amd1, was repressed at the level of protein synthesis in NPCs while mRNA levels remained the same. Amd1 is a highly conserved enzyme required for the formation of the polyamines spermine and spermidine. These polyamines are small positively charged molecules that are essential in all cells and are known to regulate a wide array of processes. They are believed to exist predominantly in complexes with mRNA and DNA and have been demonstrated to regulate gene expression at the transcription, translation and mRNA stability level.
The authors show that the translational repression of Amd1 is mediated by a specific microRNA that is selectively up-regulated in NPCs. This resulted in a dramatic reduction of Amd1 protein levels in NPCs. Failure to translationally down regulate Amd1 resulted in continued expression of the protein and a failure in NPC differentiation. This data provides an example of how miRNA mediated regulation of an mRNA is essential for early neural differentiation.