Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

No getting around RET

18.11.2004


Researchers find no role for RET-independent GFR-alpha in development or regeneration

Neurons depend on external molecular signals for their very survival. These molecules, collectively referred to as neurotrophic factors, include a family of four GDNF Family Ligands (GFLs) that bind to specific receptor sites on the surfaces of neural cells. These sites allow GFLs to signal through a receptor complex composed of the RET tyrosine kinase and a GFRá-family receptor. Tyrosine kinases, such as RET, are well-known for their function in phosphorylation cascades that span the cell membrane. The role of the GFRá co-receptors in these complexes was long thought to be limited to as a co-receptor for RET, but GFRs have recently been suggested to play other roles as well.

The individual functions of the RET and GFRá subunits in these receptor complexes, which are important in developmental milieux from peripheral neurogenesis to the developing kidney, remains a thorny question complicated by the fact that GFRá is much more widely expressed in the body than is RET and that, in vitro, cells expressing GFRá1 without RET have been shown to respond to GDNF signals. A report by Hideki Enomoto (Team Leader, Laboratory for Neuronal Differentiation and Regeneration) and colleagues at the RIKEN Center for Developmental Biology and the Washington University School of Medicine published in the November 18 issue of Neuron now challenges the view that RET-independent GFRá1 signaling plays a significant physiological role in either development or regeneration.



Enomoto first devised an elegant experimental system to make it possible to generate mice specifically lacking RET-independent GFRá1. The study of GFRá deficiencies in vivo is dogged by the lethality of the phenotype, in which the absence of enteric neurons and functioning kidneys results in death soon after birth. In vitro studies and the proximity of RET-independent GFRá and RET-expressing cells in some developmental regions, however, have prompted strong speculation that GFRá might be able to operate even in the absence of RET indigenous to the cell. It has been suggested that this might take the form of either trans signaling, in which the GFRá receptor captures diffusible GFLs and presents them to a neighboring RET-expressing cell, or through a separate signaling mechanism mediated by GFL-activated neural cell adhesion molecules (NCAMs).

Given this body of work showing the likelihood of a physiological role for RET-independent GFRá1 activity, Enomoto et al. decided to test whether the in vitro evidence would be borne out in living mice. The team first showed that mice homozygous for a transgene deleting an important segment of the GFRá1 gene died in the perinatal period, while heterozygotes (which carried only a single copy of the transgene) were healthy and fertile. On comparing specific embryonic regions in hetero- and homozygous mice, they found associations between RET-expressing and RET-independent GFRá1 cells in kidney, enteric and motor neurons, as well as the expected disturbances in development. However, when they next generated mice that were only capable of expressing GFRá1 only in the RET-expressing cells (by cloning GFRá1 cDNA into a region under the control of the Ret promoter and crossbreeding the resulting animals with GFRá1 heterozygotes), they were surprised to discover the mice were born healthy and free of any evident developmental defects in the kidney or nervous system. They found no trace of GFRá1 mRNA in non-Ret-expressing cells in these mice (which they named Cis-only mice, for their lack of trans signaling), while GFRá1 transcripts were detected as expected in RET-positive cells, proving that the conditional expression scheme had worked.

Analysis of individual regions known to be susceptible developmental failure on loss of GFRá1 function, such as the kidneys, motor and enteric neurons and certain parts of the central nervous system during development and following injury, showed that Cis-only mice develop and regenerate structures that are both morphologically normal and fully functional.

Investigating the second question of a possible alternate RET-independent GDNF receptor complex thought to involve neural cell adhesion molecules, they next examined Cis-only mouse olfactory bulbs. These bulbs are reduced in size in NCAM-deficient mice as the result of impaired migration of neural precursors through a zone called the rostral migratory stream and swell with cells that have failed to reach their normal destination; this phenotype is seen in mice only weakly lacking GFRá1 (which is thought by some to regulate NCAM-mediated cell adhesion), but not in mice lacking RET. Again, the Cis-only mice showed no discernible differences from wild type.

This comprehensive series of experiments makes a convincing case against any essential physiological role for RET-independent GFRá1, but leaves the question of why GFRá1 would be more widely expressed if it indeed plays no role without RET. It may be the case that GFRá receptors associate with other partners that have yet to be identified. Whatever the answer, by laying to rest a theory that had been strongly supported by in vitro evidence, the Enomoto report serves to underscore the importance of differences between the behavior of cells in the body and cells in a dish.

Doug Sipp | EurekAlert!
Further information:
http://www.riken.jp

More articles from Life Sciences:

nachricht Nerves control the body’s bacterial community
26.09.2017 | Christian-Albrechts-Universität zu Kiel

nachricht Ageless ears? Elderly barn owls do not become hard of hearing
26.09.2017 | Carl von Ossietzky-Universität Oldenburg

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: The fastest light-driven current source

Controlling electronic current is essential to modern electronics, as data and signals are transferred by streams of electrons which are controlled at high speed. Demands on transmission speeds are also increasing as technology develops. Scientists from the Chair of Laser Physics and the Chair of Applied Physics at Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) have succeeded in switching on a current with a desired direction in graphene using a single laser pulse within a femtosecond ¬¬ – a femtosecond corresponds to the millionth part of a billionth of a second. This is more than a thousand times faster compared to the most efficient transistors today.

Graphene is up to the job

Im Focus: LaserTAB: More efficient and precise contacts thanks to human-robot collaboration

At the productronica trade fair in Munich this November, the Fraunhofer Institute for Laser Technology ILT will be presenting Laser-Based Tape-Automated Bonding, LaserTAB for short. The experts from Aachen will be demonstrating how new battery cells and power electronics can be micro-welded more efficiently and precisely than ever before thanks to new optics and robot support.

Fraunhofer ILT from Aachen relies on a clever combination of robotics and a laser scanner with new optics as well as process monitoring, which it has developed...

Im Focus: The pyrenoid is a carbon-fixing liquid droplet

Plants and algae use the enzyme Rubisco to fix carbon dioxide, removing it from the atmosphere and converting it into biomass. Algae have figured out a way to increase the efficiency of carbon fixation. They gather most of their Rubisco into a ball-shaped microcompartment called the pyrenoid, which they flood with a high local concentration of carbon dioxide. A team of scientists at Princeton University, the Carnegie Institution for Science, Stanford University and the Max Plank Institute of Biochemistry have unravelled the mysteries of how the pyrenoid is assembled. These insights can help to engineer crops that remove more carbon dioxide from the atmosphere while producing more food.

A warming planet

Im Focus: Highly precise wiring in the Cerebral Cortex

Our brains house extremely complex neuronal circuits, whose detailed structures are still largely unknown. This is especially true for the so-called cerebral cortex of mammals, where among other things vision, thoughts or spatial orientation are being computed. Here the rules by which nerve cells are connected to each other are only partly understood. A team of scientists around Moritz Helmstaedter at the Frankfiurt Max Planck Institute for Brain Research and Helene Schmidt (Humboldt University in Berlin) have now discovered a surprisingly precise nerve cell connectivity pattern in the part of the cerebral cortex that is responsible for orienting the individual animal or human in space.

The researchers report online in Nature (Schmidt et al., 2017. Axonal synapse sorting in medial entorhinal cortex, DOI: 10.1038/nature24005) that synapses in...

Im Focus: Tiny lasers from a gallery of whispers

New technique promises tunable laser devices

Whispering gallery mode (WGM) resonators are used to make tiny micro-lasers, sensors, switches, routers and other devices. These tiny structures rely on a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

“Lasers in Composites Symposium” in Aachen – from Science to Application

19.09.2017 | Event News

I-ESA 2018 – Call for Papers

12.09.2017 | Event News

EMBO at Basel Life, a new conference on current and emerging life science research

06.09.2017 | Event News

 
Latest News

Nerves control the body’s bacterial community

26.09.2017 | Life Sciences

Four elements make 2-D optical platform

26.09.2017 | Physics and Astronomy

Goodbye, login. Hello, heart scan

26.09.2017 | Information Technology

VideoLinks
B2B-VideoLinks
More VideoLinks >>>