How developing visual system axons stay in the correct layer

December 8, 2017, Tokyo Institute of Technology
During the pupal stage, photoreceptors extend the axons into the brain region called medulla which has layered structure. All the photoreceptor axons are labeled in red, and R7 photoreceptor axons are specifically labeled in green. Optic lobes in the brain are labeled in blue. At this stage (24 hours after puparium formation), the R7 axon terminals reaching the single specific layer can be observed (green). Credit: Takashi Suzuki

Scientists at Tokyo Tech have made an important discovery concerning the development of layer-specific axonal connections in the developing visual system of Drosophila flies. This discovery provides valuable insights into how neurons in the developing brain are wired. The molecular mechanisms we found can serve as a universal principle for wiring axons also in higher animals. We assume our findings help stabilize the regenerating axons to the desired depth in the brain layers, in the case such as neuronal transplantation after injury.

Drosophila flies, which are a common model organism in laboratory research, have a layered visual system, just like other animals, including humans. For the visual system to function properly, each layer must receive specific connections from particular neuron populations. For this to happen, axons in the developing nervous system must grow to their target layers and then form stable connections there.

To identify how these stable connections form, Takashi Suzuki's group investigated the roles of two proteins, called LAR and Ptp69D, that are necessary for a group of light-sensitive cells called R7 photoreceptors to correctly project axons to the sixth layer (M6) of a visual area called the medulla in Drosophila brains. Their work is published in eLife.

The group first created double-mutant embryonic flies in which the R7 photoreceptors did not express the LAR and Ptp69D genes. In these flies, over 80% of R7 axons failed to terminate within the M6 layer. The axons would initially reach the M6 layer, but as development progressed, they frequently retracted and exited the medulla entirely.

To wire the neuronal connection, the axons are first attracted then stabilize. LAR and Ptp69D are required only for the stabilization. Credit: Takashi Suzuki

Next, they used a temperature-controlled gene expression system to determine how cumulative LAR and Ptp69D expression affected layer-specific termination of the R7 axons. At the lowest cumulative expression level, almost all R7 axons terminated outside the medulla, but as cumulative expression levels were increased towards normal physiological levels, it became common for R7 axons to terminate in the M6 layer.

They continued their research by selectively reintroducing LAR or Ptp69D in the double-mutant flies. Reintroducing either protein restored R7 axon termination in the medulla, but this rescue effect was inhibited when the scientists used mutations to delete parts of the restored proteins that affect functions within the neurons. This suggests that intracellular signaling from LAR and Ptp69D plays a key role in forming stable connections in the medulla.

Interestingly, restoring LAR resulted in R7 axons mainly terminating in layers M0 and M6, whereas restoring Ptp69D resulted in R7 axons terminating in layer M3. Proteins like LAR and Ptp69D bind to target molecules called ligands, and this observation suggests that layers M0 and M6 contain ligands for LAR and that layer M3 contains ligands for Ptp69D. The presence of appropriate ligands would cause LAR and Ptp69D to form stable connections for the R7 axons.

Taken together, these results provide important insights into how axon projections are targeted in the developing visual system. The effects of LAR and Ptp69D were both additive, in that cumulative expression determined the accuracy of axon targeting to the medulla, and protein-specific, in that LAR and Ptp69D tended to guide the to different layers in the medulla. A major task for future studies will be to identify the LAR and Ptp69D ligands that are hypothesized to mediate this layer-specific targeting.

The final stabilizing layer of the R7 photoreceptor axons are determined by the cumulative activity of LAR and Ptp69D. Credit: Takashi Suzuki

Explore further: Neural connections mapped with unprecedented detail

More information: Satoko Hakeda-Suzuki et al, Two receptor tyrosine phosphatases dictate the depth of axonal stabilizing layer in the visual system, eLife (2017). DOI: 10.7554/eLife.31812

Related Stories

Neural connections mapped with unprecedented detail

July 4, 2016
A team of neuroscientists at the Champalimaud Centre for the Unknown, in Lisbon, has been able to map single neural connections over long distances in the brain. "These are the first measurements of neural inputs between ...

The nerve-guiding 'labels' that may one day help re-establish broken nervous connections

August 16, 2017
Scientists have identified a large group of biological 'labels' that guide nerves to ensure they make the correct connections and control different parts of the body. Although their research was conducted with fruit flies, ...

Identification tags define neural circuits

December 17, 2015
The human brain is composed of complex circuits of neurons, cells that are specialized to transmit information via electrochemical signals. Like the circuits in a computer, these neuronal circuits must be connected in particular ...

New microdevice prepares axon fascicles in the lab like those seen in the brain

October 26, 2017
Axons are the structures through which neurons transmit information to other cells. In the body, they aggregate to form fascicles. Several technologies allow scientists to generate and study single axons in the lab, but none ...

Deciphering the role of brain layers

November 19, 2015
New research from the Department of Developmental Neurobiology at the Institute of Psychiatry, Psychology & Neuroscience, King's College London, sheds light into the role of layers in the brain. The study, published today ...

Recommended for you

Scientists identify method to study resilience to pain

December 14, 2018
Scientists at the Yale School of Medicine and Veterans Affairs Connecticut Healthcare System have successfully demonstrated that it is possible to pinpoint genes that contribute to inter-individual differences in pain.

Parents' brain activity 'echoes' their infant's brain activity when they play together

December 13, 2018
When infants are playing with objects, their early attempts to pay attention to things are accompanied by bursts of high-frequency activity in their brain. But what happens when parents play together with them? New research, ...

Researchers find the cause of and cure for brain injury associated with gut condition

December 13, 2018
Using a mouse model of necrotizing enterocolitis (NEC)—a potentially fatal condition that causes a premature infant's gut to suddenly die—researchers at Johns Hopkins say they have uncovered the molecular causes of the ...

In the developing brain, scientists find roots of neuropsychiatric diseases

December 13, 2018
The most comprehensive genomic analysis of the human brain ever undertaken has revealed new insights into the changes it undergoes through development, how it varies among individuals, and the roots of neuropsychiatric illnesses ...

Researchers discover abundant source for neuronal cells

December 13, 2018
USC researchers seeking a way to study genetic activity associated with psychiatric disorders have discovered an abundant source of human cells—the nose.

How the brain tells you to scratch that itch

December 13, 2018
It's a maddening cycle that has affected us all: it starts with an itch that triggers scratching, but scratching only makes the itchiness worse. Now, researchers have revealed the brain mechanism driving this uncontrollable ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.