Summary: Researchers report polarized phosphorylation of shootin 1 within growth cones is required for the directional axon guidance induced by netrin-1 gradients.
While today’s technology is growing increasingly wireless, nature’s greatest technology, the human brain, still depends on neurons being directly connected to one another. Two neurons are connected when one extends its axon to the other. This extension is activated by chemical cues that causes the axon to exert a directional force towards the proper direction. While scientists have long known of different molecules that can act as cues, the molecules that initiate the force have remained a mystery. In a new study published in eLIFE, a team of Japanese and American scientists report that shootin1 is one such molecule and is essential for guiding the axon to its final destination.
Naoyuki Inagaki, Professor at the Nara Institute of Science and Technology (NAIST) and leader of the study, explains that there are two molecules that have vital roles in axon guidance.
“Nectin-1 is a well characterized axon guidance molecule. Shootin1 is a brain-specific protein involved in axon outgrowth.”
Concentration changes in nectin-1 cause an axon to change its direction of growth with such abruptness that under a microscope it almost seems like someone is controlling the axon with a steering wheel. However, just how big an effect shocked even the scientists.
“We found that a slight concentration gradient in netrin-1 of only 0.4% induces a 71% difference in shootin1a phosphorylation within growth cones,” says Dr. Kentarou Baba, who first-authored the study. “That is remarkable sensitivity.”
That means even if the difference between the amount of nectin-1 on the two sides of the growth cone was less than 1%, more than two-thirds of phosphorylated shootin1 would accumulate on the side with more nectin-1, and thus steer the axon to its proper direction.
Further, the phosphorylation significantly enhanced the binding of shootin1 to L1-CAM, a molecule which Inagaki says “are the wheels of the axon.” The axons could still grow if the interaction between shootin1 and L1-CAM was disrupted, albeit at a slower velocity, but not in the direction signaled by the nectin-1 gradient.
“The direct interaction between shootin1 and L1-CAM generated the traction force for growth cone motility,” says Baba.
The findings suggest that shootin1 is a natural chemo-mechanical transducer, converting chemical information into mechanical output.
“Our findings suggest that the polarized phosphorylation of shootin1 within growth cones is required for the directional axon guidance induced by netrin-1 gradients,” says Inagaki.
Funding: Japan Society for the Promotion of Science, Japan Agency for Medical Research and Development, Osaka Medical Research Foundation for Incurable Diseases, Takeda Science Foundation funded this study.
Source: Takahito Shikano – NARA
Publisher: Organized by NeuroscienceNews.com.
Image Source: NeuroscienceNews.com image is credited to Naoyuki Inagaki.
Original Research: Open access research for “Gradient-reading and mechano-effector machinery for netrin-1-induced axon guidance” by Kentarou Baba, Wataru Yoshida, Michinori Toriyama, Tadayuki Shimada, Colleen F Manning, Michiko Saito, Kenji Kohno, James S Trimmer, Rikiya Watanabe, and Naoyuki Inagaki in eLife. Published August 7 2018.
Gradient-reading and mechano-effector machinery for netrin-1-induced axon guidance
Growth cones navigate axonal projection in response to guidance cues. However, it is unclear how they can decide the migratory direction by transducing the local spatial cues into protrusive forces. Here we show that knockout mice of Shootin1 display abnormal projection of the forebrain commissural axons, a phenotype similar to that of the axon guidance molecule netrin-1. Shallow gradients of netrin-1 elicited highly polarized Pak1-mediated phosphorylation of shootin1 within growth cones. We demonstrate that netrin-1–elicited shootin1 phosphorylation increases shootin1 interaction with the cell adhesion molecule L1-CAM; this, in turn, promotes F-actin–adhesion coupling and concomitant generation of forces for growth cone migration. Moreover, the spatially regulated shootin1 phosphorylation within growth cones is required for axon turning induced by netrin-1 gradients. Our study defines a mechano-effector for netrin-1 signaling and demonstrates that shootin1 phosphorylation is a critical readout for netrin-1 gradients that results in a directional mechanoresponse for axon guidance.