In the new study, the researchers identified a molecular program that controls an essential step in the fast-growing brains of young mammals. The researchers found that this signaling pathway spurs the growth of neuronal output connections by a mechanism called “mitochondrial capture,” which has never been described before.
“Mutations that may affect this signaling pathway already have been found in some autism cases,” said TSRI Professor Franck Polleux, who led the research, published June 20, 2013 in the journal Cell.
Further experiments by Courchet showed that LKB1 drives axonal branching by activating another kinase, NUAK1. The next step was to try to understand how this newly identified LKB1-NUAK1 signaling pathway induced the growth of new axon branches.
Stopping the Train in Its Tracks
Following a thin trail of clues, the researchers decided to look at the dynamics of microtubules. These tiny railway-like tracks are laid down within axons for the efficient transport of molecular cargoes and are altered and extended during axonal branching. Although they could find no major change in microtubule dynamics within immature axons lacking LKB1 or NUAK1, the team did discover one striking abnormality in the transport of cargoes along these microtubules. Tiny oxygen-reactors called mitochondria, which are the principal sources of chemical energy in cells, were transported along axons much more actively—and by contrast, became almost immobile when LKB1 and NUAK1 were overexpressed.
But the LKB1-NUAK1 signals weren’t just immobilizing mitochondria randomly. They were effectively inducing their capture at points on the axons where axons form synaptic connections with other neurons. “When we removed LKB1 or NUAK1 in cortical neurons, the mitochondria were no longer captured at these points,” said Tommy Lewis, Jr., a research associate in the Polleux Laboratory who was co-lead author of the study.
“We argue that there must be an active ‘homing factor’ that specifies where these mitochondria stop moving,” said Polleux. “And we think that this is essentially what the LKB1-NAUK1 signaling pathway does here.”
Precisely how the capture of mitochondria at nascent synapses promotes axonal branching is the object of a further line of investigation in the Polleux laboratory. “We think that we have uncovered something very interesting about mitochondrial function at synapses,” Polleux said.
In addition to its basic scientific importance, the work is likely to be highly relevant medically. Developmentally related brain disorders such as epilepsy, autism and schizophrenia typically involve abnormalities in neuronal connectivity. Recent genetic surveys have found NUAK1-related gene mutations in some children with autism, for example. “Our study is the first one to identify that NUAK1 plays a crucial role during the establishment of cortical connectivity and therefore suggests why this gene might play a role in autistic disorder,” Polleux says.
He notes, too, that declines in normal mitochondrial transport within axons have been observed in neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. “In the light of our findings, we wonder if the decreased mitochondrial mobility observed in these cases might be due not to a transport defect, but instead to a defect in mitochondrial capture in aging neurons,” he said. “We’re eager to start doing experiments to test such possibilities.”
Other contributors to the study, “Terminal Axon Branching Is Regulated by the LKB1-NUAK1 Kinase Pathway via Presynaptic Mitochondrial Capture,” were Sohyon Lee, Virginie Courchet and Deng-Yuan Liou of TSRI, and Shinichi Aizawa of the RIKEN Institute of Kobe, Japan.
The study was funded in part by the National Institutes of Health (grants R01AG031524 and 5F32NS080464), ADI-Novartis, Fondation pour la Recherche Medicale, and the Philippe Foundation.
About The Scripps Research Institute
The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs about 3,000 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists—including three Nobel laureates—work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see www.scripps.edu.
Mika Ono | Newswise
Smart Data Transformation – Surfing the Big Wave
02.12.2016 | Fraunhofer-Institut für Angewandte Informationstechnik FIT
Climate change could outpace EPA Lake Champlain protections
18.11.2016 | University of Vermont
Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...
A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.
Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...
In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.
“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...
The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.
The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...
Broadband rotational spectroscopy unravels structural reshaping of isolated molecules in the gas phase to accommodate water
In two recent publications in the Journal of Chemical Physics and in the Journal of Physical Chemistry Letters, researchers around Melanie Schnell from the Max...
16.11.2016 | Event News
01.11.2016 | Event News
14.10.2016 | Event News
05.12.2016 | Power and Electrical Engineering
05.12.2016 | Materials Sciences
05.12.2016 | Power and Electrical Engineering