Expression patterns of each of the proteins [Nkx2.2 (red), Pax6 (green) and Isl1 (blue)] visualized above falls under the influence of sonic hedgehog (yellow).
Photo: J. Ericson

Sonic Hedgehog
and Its Cohorts

Prior to the ETS studies, Jessell and a small group of colleagues revealed how an embryonic protein called sonic hedgehog simultaneously directs several routes of differentiation. Sonic hedgehog was discovered in 1993, and studies of the protein have since revealed a wealth of information about the nervous system.

Neuroscientists had already demonstrated that the chemical messenger that launches motor neurons on the path to differentiation comes from the notochord. Now researchers know that the molecule responsible is none other than sonic hedgehog–named for the bristly appearance of fruit flies that lack the related hedgehog gene. (The "sonic" part of the name, which denotes the mammalian version of the previously discovered fruit fly gene, arose thanks to scientific humor and a love of video games.)

Sonic hedgehog is a secreted extracellular protein that transmits its signal by binding to a receptor on the surface of a cell. That binding, in turn, propagates the signal to the interior of the cell. Once inside, the signal activates a variety of genes that begin to change a generic neuron into a motor neuron.

Sonic hedgehog’s range of influence on embryonic cells is sweeping, exerting its effects in a dose-dependent fashion. This means that the amount of sonic hedgehog to which an embryonic cell is exposed determines the cell’s fate. Of particular interest to Jessell are two parallel bands of cells at an intermediate distance from the notochord that receive a small dose of sonic hedgehog. That dose of sonic hedgehog is enough to direct these cells become motor neurons. In the October 2, 1998, issue of Cell, Jessell’s group reported that one of sonic hedgehog’s main functions for developing motor neurons is to activate a homeobox gene called MNR2. "The important thing about MNR2 is that it begins to be expressed earlier than other motor neuron genes. It is probably one of the first targets of transcription that is dependent on sonic hedgehog," Jessell says.

The study of MNR2, which Jessell conducted with associates Yasuto Tanabe and Christopher William, demonstrates that as long as neural progenitor cells express MNR2, motor neurons arise—even in the absence of sonic hedgehog. This suggests that MNR2 alone is sufficient for motor neuron differentiation, Jessell explains.

"This finding may have implications beyond simply the study of motor neurons," Jessell points out. "Results with MNR2 raise the possibility that there may be single transcription factors that are sufficient to control the differentiation of other classes of neurons in the CNS—for example, the dopamine neurons that degenerate in Parkinson’s disease. If you are trying to reconstruct a circuit that’s defective as a result of neurodegeneration, you need to know how many factors you need to restore that particular neuron. It could be many. But this research begins to suggest there could be single genes that direct particular neuronal fates. The idea eventually would be to introduce such genes into a progenitor cell in vitro and direct the differentiation of specific cell types."

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