How neurons remain neurons

A short Feb ’11 review by Oliver Hobert (HT: J Snyder) explains the process. A particular protein called a terminal selector coordinates it, and acts by binding to DNA sequences. One might describe the process as involving three main steps:

1) Initiation. Initiation occurs when neuroblasts terminally divide. An initiator protein binds to the DNA upstream of the gene encoding the terminal selector (in particular, to the “cis-regulatory element” of the DNA). This activates transcription of the terminal selector, and thus its translation as well. Crucially, the initiator protein is itself only expressed for short window of time.

2) Propagation. The terminal selector binds to the cis-regulatory elements upstream of “terminal differentiation genes,” activating their expression. These genes are involved in neural function, such as neurotransmitter metabolism and ion channels. Some also presumably act to arrest the cell’s growth phase in G0.

3) Maintenance. Through a common mechanism known as transcriptional autoregulation, the terminal selector gene maintains its levels by binding to a cis-regulatory element upstream of its own gene, thus activating its own expression. So, long after the initiator protein is no longer present (and indeed for the lifespan of the animal), the expression of the terminator selector gene will remain high, and it will, in turn, continue to activate the expression of the terminal differentiation genes.

This is also an interesting case study in the interplay between chromatin states and the action of transcription factors. New (“de novo”) events of transcription factor binding require the chromatin to “open up” to allow them to bind the DNA. An individual transcription factor protein molecule probably only binds to the DNA for short periods of time (low dissociation constants suggest it’s often on the scale of milliseconds). This also leads to remodeling of the chromatin state via histone modifications, which over the long run might make binding of the transcription factors easier.

But how important are the relative contributions of de novo transcription factor binding, histone modifications, and the initial chromatin state of DNA upstream the terminator selector and terminal differentiation genes? As far as I can tell, these remain somewhat pressing and open questions.

References

Holbert O, 2011, Maintaining a memory by transcriptional autoregulation, Current Biology. doi:10.1016/j.cub.2011.01.005

Kiełbasa SM, Vingron M (2008) Transcriptional Autoregulatory Loops Are Highly Conserved in Vertebrate Evolution. PLoS ONE 3(9): e3210. doi:10.1371/journal.pone.0003210

Wang Y, et al. 2009 Quantitative Transcription Factor Binding Kinetics at the Single-Molecule Level. Biophys Journal 10.1016/j.bpj.2008.09.040.