The rainbow and the brain

The rainbow and the brain


Recently, we met two very bright rodent brains: one is the Ratatouille mouse by Pixar, the other one is Brainbow (Rainbow Mouse Brain) by Jean Livet and colleagues from Harvard University. In November 2007, Nature published spectacular, colourful pictures of neurons and their axon and dendrites. In the brainbow mouse, each neuron can randomly dress 90 different colors. Each color is generated by the combination of 3-4 GFP variants following the same mechanism that your iPad use to obtain a wide color space just by mixing three primary channels (red, green and blue), but in the rodent, the pixels are actually neurons and the primary channels are fluorescent proteins.
How to make a Brainbow. Basically, a transgenic mouse expressing Cre recombinase, is mated with another transgenic mouse in which a CMV/thy1 promoter expresses an array of 3 or 4 GFP color variants placed between different sets of incompatible lox sites. In each neuron (Thy1 promoter) of the progeny, Cre recombinase is forced to choose between two mutually exclusive excision events (lox). The random recombination event generates a panel of neurons that massively express one, or two, or three fluorescent proteins of different colors. Finally, the colored light of each GFP protein merges generating roughly 90 different hues, which can be observed by fluorescence imaging.

Which progress would bring that mouse to neuroscience? Why one scientist should use this mouse to track single neurons in a brain section when a black stain, the Golgi-Cajal stain, is already in use since 1873? The answer can be found in large-scale systems biology: with the Brainbow colors it is possible to follow each neuron (and possibly each connection that thousands of neurites belonging to a single neuron can develop). By doing so, we could try to obtain "connectomic maps" of the brain. In addition, since the color of the neuron remains the same, why do not better explore brain development with some highly-rendered lineage analysis? What about probing individual regenerative events after spinal cord injuries? The spectra of investigational opportunities seems quite large considered that we are just dealing with an old reporter drived by a common CMV promoter. And, in case I'm wrong, the Brainbow mouse remains a memorial to the best GFP imaging ever.

---/ Source. The Brainbow mouse has been first described in: Livet, J., Weissman, T., Kang, H., Draft, R., Lu, J., Bennis, R., Sanes, J., & Lichtman, J. (2007). Transgenic strategies for combinatorial expression of fluorescent proteins in the nervous system - Nature, 450 (7166), 56-62 - doi:10.1038/nature06293

Follow up updates

A Brainbow with wrist-watch. In Hungary, time-shifted GFP colors have beed added to a sort of Brainbow-like mice. 4D connectomics in space and time is now possible. --> 
Not only mice: Flybow fruit-flies (D. melanogaster) are out now, read the news at Brainwindows. Some other beautiful Brainbow pictures freely available in a Cell Picture Show.
Multicolor Zebrafish. Lineage analysis with Brainbow Zebrafish reveals stem-cell clonal selection possibilities for organ development.
Brainbow mice are used to prototype 3-photon microscopy to image deeper in the brain (see labrigger notice)