New study presents surprising view of brain formation

February 9, 2011

Embargoed by the journal Neuron until February 9, 2011, noon, Eastern time – A study from The Scripps Research Institute has unveiled a surprising mechanism that controls brain formation. The findings have implications for understanding a host of diseases, including some forms of mental retardation, epilepsy, schizophrenia, and autism.

The research, led by Scripps Research Professor Ulrich Mueller, was published in the journal Neuron on February 10, 2011.

In the new study, Mueller and colleagues focused on a protein called reelin. They found reelin is a key player in the migration of new nerve cells to the neocortex, the part of the brain responsible for higher-order functions, such as language and movement.

Unexpectedly, the scientists also found reelin affects this migration process independent of glial cells, which often act to guide such nerve cell movement.

A Critical Migration

As the human brain develops, newly formed nerve cells travel from their place of origin to different brain regions. Once they reach their appropriate destination, nerve cells connect to one another to form the intricate circuits and networks responsible for various brain functions. Anything that disrupts the course of this nerve cell migration results in an improperly formed brain—and the consequences are typically devastating.

More than 50 years ago, researchers discovered a type of mutant mouse with a neocortex and cerebellum that were inaccurately organized, affecting the animal's ability to walk normally. Later, researchers discovered that this mouse, called "reeler" because of its reeling gait, was affected by a mutation in a particular gene, dubbed reelin, which encodes a protein produced by nerve cells.

The human counterpart of the gene is mutated in children with lissencephaly—literally "smooth brain"—a condition that results in a brain that lacks its characteristic folds. Reelin mutations have also been identified in children with an abnormally small brain, or microcephaly.

Although these observations indicate reelin must play a key role in proper brain formation, until now no one knew exactly what that role was.

Probing Reelin Function

Since the identification of the reelin gene in 1995, researchers discovered that the corresponding protein is released by certain nerve cells and binds to receptors on other nerve cells. This binding then triggers a cascade of chemical reactions, or a signaling pathway, in the nerve cell. Such signaling pathways eventually produce a change in the target cell; they are one of the ways in which cells respond to stimuli in their environment.

"We knew that reelin binds to several receptors on nerve cells and initiates different signaling pathways, but one question we wanted to ask was 'Do these pathways regulate migration?'" said Mueller. "And if they do, how?"

To start answering these questions, the group combined several technologies that have become available in recent years. The scientists labeled nerve cells in the brains of mouse embryos with fluorescent dyes and then, using special microscopes, watched these cells move in real time in the neocortex of the brain.

In this way, Mueller's team compared the movement of nerve cells in normal mice, with an intact reelin pathway, and mutant mice, in which the reelin signaling pathways had been blocked. The scientists were surprised by what they saw.

Following Cell Tracks

Researchers had long known that newly formed nerve cells crawl along a particular type of cell in the brain, called a glial cell, which acts as a cellular guide for the nerve cells. But in recent years, studies revealed that some nerve cells can find their destination independently of glial direction. These nerve cells grow an arm that reaches out to find the correct path and then the cell's body follows along.

Researchers in the field had assumed that the formation of the neocortex involved the first strategy: glial-directed migration. But through their imaging studies, Mueller and colleagues found that the opposite was true. They discovered that when the reelin pathway is inactivated in nerve cells, these cells no longer migrate to the appropriate spots in the neocortex, as they do in normal mice. However, these nerve cells don't move by following glial guides, but rather by relying on their own devices.

"Reelin does not affect glial-directed migration, but a reelin mutation still messes up brain architecture," said Mueller.

This finding implies that glial-independent migration is much more important to neocortex formation than scientists had envisioned and that reelin somehow controls this process.

Finding Disease Genes

Although the mechanism by which reelin affects migration is not fully understood, Mueller's group has identified some of the molecules reelin "talks" to in order to produce its effect.

Another well-known class of molecules that play a role in formation consists of the cadherins—these proteins provide a molecular "glue" for cells to stick to one another as they move. Mueller and colleagues showed that reelin controls the function of cadherins in .

Future studies should identify additional players. And, as these new molecules are discovered, Mueller plans to collaborate with geneticists to look for mutations in the corresponding genes in people.

"We might find additional genes involved in schizophrenia and autism," he said. "We already know that some cadherins are involved in autism spectrum disorder."

More information: "Reelin regulates cadherin function via Dab1/Rap1 to control neuronal migration and lamination in the neocortex," by Santos J. Franco et al., Neuron, February 10, 2011.

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1 / 5 (14) Feb 09, 2011
So how many organisms were brainless or brain-dead and became extinct because of the wrong mutation whilst the "right" mutation finally came along?

Surely, by now evolutionists should be running for the darkest shadows because they have no way to explain how the brain evolved from nothing. How on earth did the nerve cells get put into place and then survive without the blood supply? And how did the blood supply survive without the immune system to guard it from contamination? And how did the immune system function without the various detection mechanisms in place?
Serious questions that need to be answered by evolutionisti.
5 / 5 (5) Feb 09, 2011

Serious questions that need to be answered by evolutionisti.

Answers that probably already exist and that you will certainly ignore. You....are....pathetic.
5 / 5 (6) Feb 09, 2011
Seriously kevin, you've yet to make any kind of a point that gives evolutionists the slightest problem; you've proven your total ignorance of basic science time after time after time; You get shot down every time you post, sometimes embarrassingly so. Why do you keep it up? Do you think, like the JWs, that you get "points" for trying? Do you actually think you're going to convince anyone of anything other than that croetards are, well, morons? Seriously, this isn't a rhetorical question. What's your motivation for continuing this constant fail? Are you being paid for it? (I could at least understand that).
5 / 5 (6) Feb 09, 2011
So how many organisms were brainless or brain-dead and became extinct because of the wrong mutation

Probably quite many. Thing is, for those unfortunate creatures to exist, there has to be many more with a working version of the gene who survived to breed. The braindead mutants didn't just pop out of nothingness.

For a species to survive, its genetics has to be robust enough to keep those who are born "brainless" in the minority, and in fact such is the case. We know that individual amino-acid pairs in the genes work as triplets, where flipping any one pair will not change the protein that is produced, and a gene sequence will not depend on just one triplet but many repeating ones, which gives it at first error correction, and when that fails, redundancy.

The wrong protein that is created when one triplet in the sequence fails will therefore not affect the function of the whole sequence very much, and it may instead provide a starting point for a new function to evolve.
5 / 5 (5) Feb 09, 2011
You may think of it as a factory that produces door hinges. The workers follow a list that says "Make one hinge, make one hinge, make one hinge". Repeated many times over.

At some point in copying the list, someone accidentally changes one item on the list to "make one syringe", and so in the pile of a thousand hinges, there will be one syringe, but that doesn't matter since they're producing more hinges than doors anyways. They can simply scrap the syringe along with the hinges that they didn't use.

Then it turns out that the syringe is very useful for dropping oil in the doorhinges and as a result, everyone is better off because the hinges last longer, and the company beats its competitors because it can make better doors.
5 / 5 (4) Feb 09, 2011
Or, if a species is very simple, like a single cell organism that has a very small genome that doesn't tolerate much errors or it will stop functioning, the organism has but one option to survive as a species: breed so fast that the rate of copying exceeds the rate of harmful mutations by a vast margin.

Many copies will die, but many more will either be intact, or have a neutral mutation, or a positive mutation that helps them survive better.

Any such species that does not do so will die out, and there will eventually be only those who dodged the bullet or developed redundancy against harmful mutations.
5 / 5 (2) Feb 09, 2011
does that creationist nut have like 10 accounts or something? Maybe he is reelin deficient. Bet he took the little bus.
5 / 5 (3) Feb 10, 2011

Surely, by now evolutionists should be running for the darkest shadows because they have no way to explain how the brain evolved from nothing.

An inability to produce a theory does not prove another. Just because you can't perceive the formation of the brain doesn't prove it can't have happened.

Protobrains were likely vascular until avascular systems proved more effective. Nerve formation likely started out small, navigating a network of maybe 100 or 1000 brain cells and expanding from there.

Realize that cellular development has occured much longer than organisms have walked on land, and there can still potentially be hundreds of millions of years between each tiny phenomenon.

It seems pretty simple to me, your own conclusions seem more like a bias personal gratification then an intelligent counter arguement.
5 / 5 (1) Feb 11, 2011
Serious questions that need to be answered by evolutionisti.

Serious questions that have been answered SATISFACTORILY and THOROUGHLY again and again and again and again and again and again and again and again and again and again and again and again and again and again and again and again and again and again and again and again and again and again and again and again and again and again and again and again and again and again and again and again and again and again and again and again and again and again and again and again and again and again and again and again and again and again and again and again and again and again and again and again and again and again and again and again and again and again and again and again and again and again and again and again and again and again and again and again and again. Not that it matters to you since you're not the slightest bit interested in facts, or debate, or anything but promoting your superstition.

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