Perhaps most questions in developmental biology are essentially the same: how do cellular proteins follow environmental cues to enable differentiation? By addressing this question for how motor neurons form, work recently published in Neuron may facilitate production of an important cell type and illuminate a more general mechanism behind a fundamental puzzle. Researchers led by Soo-Kyung Lee of Baylor College of Medicine in Houston, Texas, describe the molecular choreography between an external signal, retinoic acid, and a cellular transcription factor, Neurogenin2, that leads to motor neuron production1.

Scientists have known for some time that motor neurons develop in steps from neural stem cells, Lee explains. In the final step, motor neuron progenitor cells turn on neurogenin2 (NGN2) and are exposed to retinoic acid (RA). The cells then turn on specific motor neuron genes and grow axons that target the appropriate muscle cells. How molecular signals trigger that transition was unknown.

In a detailed series of experiments, Lee and her colleagues decoded the connections between RA signaling and NGN2. They established that, as part of the process, the CREB binding protein (CBP) attaches to motor neuron enhancer DNA sequences through a complex, supported by NGN2. The researchers then developed a mechanistic model based on these findings. First, NGN2 and a partner protein called E47 bind to the motor neuron enhancer sequence. The RA receptor (RAR) joins them to form an inactive complex. When activated by an RA signal, that complex recruits CBP. CBP activates chromatin, and motor neuron genes are transcribed.

The most surprising finding is that RAR cooperates with NGN2 directly instead of through nearby response elements within the DNA sequence, says Hynek Wichterle of the Columbia University Center for Motor Neuron Biology and Disease in New York. “Such an interaction could provide an elegant solution to the unresolved problem of how cell type and cell-stage specificity of RA signaling is achieved.” RA signaling has been implicated in a variety of programs within developing motor neurons, he adds, ranging from the initiation of neurogenesis to the diversification of motor neuron subtypes.

“It's an interesting model for how an extrinsic signal can set up a cell for selecting a particular cell identity by modifying specific chromatin loci and utilizing transcriptional factors to target those modifications,” says Daniel Lim of the University of California, San Francisco. Because RA signaling is also associated with the chromatin repressor demethylase JMJD3 in forebrain neural stem cells, he says, it would be interesting to see whether RA is also involved in signals that turn genes off. “Future studies may demonstrate that RA triggers a multitude of changes to chromatin at specific loci to determine cell fate,” Lim says.

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