Scripps Florida scientists shed new light on nerve cell growth.


Amidst the astounding complexity of the billions of nerve cells and trillions of synaptic connections in the brain, how do nerve cells decide how far to grow or how many connections to build? How do they coordinate these events within the developing brain.  In a new study, scientists from The Scripps Research Institute (TSRI) have shed new light on these complex processes, showing that a particular protein plays a far more sophisticated role in neuron development than previously thought.

The study focuses on the large, intracellular signaling protein RPM-1 that is expressed in the nervous system. The team have shown the surprising degree to which RPM-1 harnesses sophisticated mechanisms to regulate neuron development.  Specifically, the research sheds light on the role of RPM-1 in the development of axons or nerve fibres, the elongated projections of nerve cells that transmit electrical impulses away from the neuron via synapses. Some axons are quite long; in the sciatic nerve, axons run from the base of the spine to the big toe.

Collectively, the lab’s recent work offers significant evidence that RPM-1 coordinates how long an axon grows with construction of synaptic connections.  Understanding how these two developmental processes are coordinated at the molecular level is extremely challenging. The group have now made significant progress.

The study describes how RPM-1 regulates the activity of a single protein known as DLK-1, a protein that regulates neuron development and plays an essential role in axon regeneration. RPM-1 uses PPM-2, an enzyme that removes a phosphate group from a protein thereby altering its function, in combination with ubiquitin ligase activity to directly inhibit DLK-1.

Studies on RPM-1 have been critical to understanding how this conserved family of proteins works.  Because RPM-1 plays multiple roles during neuronal development, it should not be interfered with. But exploring the role of PPM-2 in controlling DLK-1 and axon regeneration could be worthwhile, and could have implications in neurodegenerative diseases.

The lab has also explored other aspects of how RPM-1 regulates neuron development. A related study, also published in PLOS Genetics, shows that RPM-1 functions as a part of a novel pathway to control β-catenin activity, this is the first evidence that RPM-1 works in connection with extracellular signals, such as a family of protein growth factors known as Wnts, and is part of larger signalling networks that regulate development. A paper in the journal Neural Development shows that RPM-1 is localized at both the synapse and the mature axon tip, evidence that RPM-1 is positioned to potentially coordinate the construction of synapses with regulation of axon extension and termination.

Source:  The Scripps Research Institute

Summary of RPM-1 signaling through the ANC-1/BAR-1 pathway.  Canonical Wnt signaling through Disheveled (Dis) and APR-1 (APC ortholog) regulates the β-catenin BAR-1. In the absence of Wnt, APR-1 is active and inhibits BAR-1. In the presence of Wnt, APR-1 is inhibited and BAR-1 activity is increased. Higher levels of BAR-1 lead to increased nuclear import and activation of the transcription factor POP-1 (TCF/LEF). We have shown that RPM-1 binds to ANC-1, and RPM-1 and ANC-1 function in the same pathway to positively regulate BAR-1 activity. RPM-1 and ANC-1 are likely to function in a protein complex at the nuclear envelope to regulate BAR-1 nuclear levels by inhibition of EMR-1. Canonical Wnt signaling is likely to act coordinately with RPM-1 and ANC-1 to regulate BAR-1 activity.  Grill et al 2014.

Summary of RPM-1 signaling through the ANC-1/BAR-1 pathway. Canonical Wnt signaling through Disheveled (Dis) and APR-1 (APC ortholog) regulates the β-catenin BAR-1. In the absence of Wnt, APR-1 is active and inhibits BAR-1. In the presence of Wnt, APR-1 is inhibited and BAR-1 activity is increased. Higher levels of BAR-1 lead to increased nuclear import and activation of the transcription factor POP-1 (TCF/LEF). We have shown that RPM-1 binds to ANC-1, and RPM-1 and ANC-1 function in the same pathway to positively regulate BAR-1 activity. RPM-1 and ANC-1 are likely to function in a protein complex at the nuclear envelope to regulate BAR-1 nuclear levels by inhibition of EMR-1. Canonical Wnt signaling is likely to act coordinately with RPM-1 and ANC-1 to regulate BAR-1 activity. Grill et al 2014.

 

 

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