Sunday, July 27, 2008

BDNF transcription puzzles

There's more news out about BDNF, a neural growth factor that plays a large role in the development of the brain, and in the operation of various brain processes, such as learning. (Previous discussion here.)

To begin with, there is the curious fact that the gene for BDNF can be transcribed into (at least) two different messenger RNA sequences – yet exactly the same protein is produced from each. In this case there are two alternative 3’ untranslated regions in the two transcripts. Since the regions are untranslated, why bother with the different transcripts?

Learning Suffers If Brain Transcript Isn't Transported Far Out To End Of Neurons (7/10/08)
Neuroscientists at Georgetown University Medical Center have solved a mystery that lies at the heart of human learning, and they say the solution may help explain some forms of mental retardation as well as provide clues to overall brain functioning.

Researchers have long puzzled over why a gene known as brain-derived neurotrophic factor (BDNF), which is crucial to the ability of neurons in the hippocampus to grow and connect to each other -- forming the basis of memory and learning -- produces two different transcripts, which then each fabricate identical proteins.

In the July 11 issue of Cell, the scientists report the answer, and it has to do with transportation. They found that the longer of the two transcripts (messenger RNAs, or mRNAs) include extra sequences that "motor" molecules attach to, in order to move the information far away from the nucleus of the cell and toward the long, tree-like branches of the nerve cell known as dendrites. There, protein-synthesizing machines use that mRNA to produce protein that helps small protrusions (called dendritic spines) on these dendrites grow.

The shorter of the mRNAs are also moved from the nucleus into the cytoplasm of the neuron, but they do not need to be transported to dendrites. These transcripts produce an identical protein, but in this case, investigators believe they help the axon, the long cable-like body of a neuron, grow.

The dendritic spines are where synapses form with the axons of other neurons, and it is the building of synapses that enables learning. Our earlier discussion noted how important BDNF is for growth of the dendritic spines.

But this research also answers a more general question about the not infrequent existence of different RNA transcripts that produce the same protein:
"The fascinating thing is that many genes produce multiple transcripts for the same protein -- and no one has known why," [lead investigator Baoji Xu] says. "So what we found here is likely very applicable to other genes. It reveals a mechanism for differential regulation of subcellular functions of proteins."

Another account of this research amplifies a few details:

If the Splice Is Right—BDNF to Dendrites, APP to Endosomes (7/11/08)
In the BDNF work, first authors Juan Ji An, Kusumika Gharami, and Guey-Ying Liao led the effort to determine whether the 3’ alternative splicing of BDNF, which has no effect on the protein coding region, was instead a way to target the message to soma versus dendrite. To do this, they first looked at localization of the splice forms and found the long form was preferentially located in dendrites in cultured rat cortical neurons. The long 3’ sequence was sufficient to target a green fluorescent protein reporter mRNA to dendrites, and that the message was translated there. ...

While the study strongly implicates dendritically targeted BDNF in the normal formation and function of spines, the data beg the question of how BDNF acts. In their discussion, the authors favor an autocrine mechanism involving activation of the TrkB receptor. In addition, they point out that the strategy of using alternative 3’UTRs to target the same protein to different subcellular localization may not be unique to BDNF.

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