Nav

Friday, May 7, 2010

Connecting Left and Right


Organisms with a bilaterally symmetric nervous system face a problem – how to integrate functions across the two sides so that behavioural outputs can be coordinated for the entire body.  In the brain this is important to allow integration of the large number of cognitive “modules” which are differentially lateralised, such as language.  (The importance of this communication is dramatically illustrated by so-called “split-brain” patients, who have had the majority of the connections between the two cerebral hemispheres severed in order to treat otherwise intractable epilepsy.  These patients, first studied by Roger Sperry and colleagues, end up in essence with two brains inside the same skull, and it could be argued, two largely independent minds). 

The importance of bilateral integration is also evident and very well understood in the control of movement, where motor commands have to be tightly and dynamically coordinated across the two sides of the body.  The integration of the two sides of the nervous system is mediated by nerve fibres that project from one side to the other.  Some neurons project axons across the midline and others do not – the binary nature of this choice has made it a favourite model system of developmental neurobiologists to investigate how growing axons are guided along specific pathways to their appropriate targets.  As a result, a great deal is known about the cellular and molecular processes that control whether an axon will cross the midline. 

The process is mediated by attractive and repulsive signals made by specialised cells which reside at the midline of the nervous system.  (Interestingly, the study of such “chemotropic” molecules was also pioneered by Sperry in a set of seminal experiments in the frog visual system).  These signals are detected by dedicated receptor proteins expressed on the surfaces of growing axons. The signals at the midline include two major families of secreted proteins: Netrins, which function to attract some neurons towards and across the midline, while repelling others, and Slits, which repel axons that normally do not cross the midline and which also prevent axons from re-crossing the midline multiple times.  How each neuron responds to these cues depends on which receptors it expresses: DCC is a receptor protein for Netrins, while Robo proteins are receptors for Slits.  Amazingly, all these proteins are very highly conserved, as are their functions in controlling axonal projections across the midline, which were discovered and elucidated in great detail in nematodes, fruit flies and mice. 

A number of studies have shown that their functions are also conserved and equally crucial in humans.  Elizabeth Engle and her colleagues found that mutations in the ROBO3 gene can lead to a condition with the unwieldy name of horizontal gaze palsy with progressive scoliosis (HGPPS).  This syndrome is characterised by an inability to coordinate the lateral movement of the eyes in the horizontal plane.  Lateral eye movements are controlled by the abducens-oculomotor nerves, one on each side of the head.  The coordination of these movements of the two eyes is mediated by a set of interneurons which normally project across the midline of the hindbrain, where the cell bodies that form these nerves are located, and coordinate the activity of the nerves on the two sides. 

As the ROBO3 gene is known to be required for axons to cross the midline, the implication was that the defect resulted from a failure to connect these cranial nerve nuclei on the two sides.  A recent study by Alain Chedotal and colleagues modeling the effects of Robo3 mutations in mice strongly supports this explanation – deletion of the gene in just that part of the hindbrain did indeed disrupt connectivity between the two sides and resulted in similar defects in horizontal eye movements in the mice. 

(If you’ve been paying attention you may be surprised that mutations in a Robo gene should cause a failure of axons to cross the midline – if the normal role of the Slit signals to which they respond is to keep axons on their own side, then mutation of a Robo gene should cause extra axons to cross the midline.  This is true for the other two Robo genes – Robo3 performs a different role, down-regulating the responses of the other Robo proteins and so mutating it has the opposite effect). 

Another study just published by Guy Rouleau and colleagues shows that the function of DCC in establishing trans-midline connectivity is also essential in humans.  They found mutations in this gene in patients with Congenital Mirror Movements.  These are involuntary movements of one side of the body that occur in response to voluntary movement of the other side – i.e., a failure to independently control and coordinate the two sides.  A similar effect has been seen in mice with mutations in this gene, which are called “Kanga” mice because of their unusual hopping gait, caused by moving both hindlimbs at the same time.  The mirror movements could be caused by a failure to project across the midline of interneurons in the spinal cord that normally inhibit movement of one side when the other side is moving. 

These studies provide a dramatic example of the importance of bilateral integration in the control of movement.  It will be interesting to investigate whether patients with these disorders also show any differences in cognitive domains which might relate to subtly altered connectivity of the two cerebral hemispheres.   

 

Srour M, Rivière JB, Pham JM, Dubé MP, Girard S, Morin S, Dion PA, Asselin G, Rochefort D, Hince P, Diab S, Sharafaddinzadeh N, Chouinard S, Théoret H, Charron F, & Rouleau GA (2010). Mutations in DCC cause congenital mirror movements. Science (New York, N.Y.), 328 (5978) PMID: 20431009

Jen, J. (2004). Mutations in a Human ROBO Gene Disrupt Hindbrain Axon Pathway Crossing and Morphogenesis Science, 304 (5676), 1509-1513 DOI: 10.1126/science.1096437

Renier N, Schonewille M, Giraudet F, Badura A, Tessier-Lavigne M, Avan P, De Zeeuw CI, & Chédotal A (2010). Genetic dissection of the function of hindbrain axonal commissures. PLoS biology, 8 (3) PMID: 20231872

17 comments:

  1. This is really interesting, I-d like to know it there are people who van connect both sides at the same time, it is just something I want to know because I read something related to that in safemeds magazine.

    ReplyDelete
  2. There is definitely so much that goes into when you brain is working. So many people do it different ways here. So much to learn from it all here. implants des sein

    ReplyDelete
  3. To write a such kind of article is really awesome,I daily read your blogs and give my announcement for that here this article is too great and so entertaining. Floor Decals

    ReplyDelete
  4. That’s been one of my mantras – focus and simplicity. Simple can be harder than complex: You have to work hard to get your thinking clean to make it simple. But it’s worth it in the end because once you get there, you can move mountains.Lush Five

    ReplyDelete
  5. My business is extremely loved due to this blog. The a informative subject matter. This support us very much to fix a few problems. The opportunity are generally therefore excellent in addition to doing work style therefore quick. I do think it usually is support everyone. Cheers For more info Click on Chicago Limousine Services

    ReplyDelete
  6. Sizzling : Assortment is often a sincere and also secret London companion agency gives authentic London escorts young ladies with regard to guys involving taste.for more info see Car dealer Tampa

    ReplyDelete
  7. The Glades is also near elite schools such as Anglican High School, St. Anthony’s Canossian Primary & Secondary School and Temasek Junior College. Tampines Junior College, Temasek Polytechnic and United World College (East Campus) is also around in the area. For vehicle owners, it takes less than 25 minutes to drive to the business hub and vibrant Orchard Road shopping district, via Pan-Island Expresswaymarion faldas

    ReplyDelete
  8. This can be a great sound judgment post. Worthwhile one who is merely seeking the means relating to this element. It's going to undoubtedly help teach me personally. Bigcommerce Offer App

    ReplyDelete
  9. To write a such kind of article is really awesome.thanks for sharing.
    HP0-Y46

    ReplyDelete
  10. The ubiquity regarding gadgets features place needs on brands along with writers to figure in concert to guarantee the complete buying expertise is actually essay writing sites to the conversion process on desktop, ipad tablet along with touch screen phones. My partner and i wanna examine much more relating to this.

    ReplyDelete
  11. There are various amateurs befitting consistent you, who are was recreant by basics of entirely a mean scam theme creating unbendings. this website It truly is trustworthy of which identifying a true creating unification seriously isn't so simple. Visceral my informative sustenance as i need lacquer my scurry do the vacancy I selected a spectacular treatise creating machine termed essayscouncil. I selected this that has a unrest planned.

    ReplyDelete
  12. the company can be at this time exploring Multilevel Oversight applying Sheffield Hal lam University along with the company can be making the exact custom made apple passbook

    ReplyDelete
  13. Few days ago I read a research created by PEW research center, they reported that Android and smart phone users go to search engine for what they want to search through their phone instead od desktop search.kennel cough

    ReplyDelete
  14. This is an interesting post. to read your post I can learn how the brain is connected in left to right.
    clipping path

    ReplyDelete
  15. This comment has been removed by the author.

    ReplyDelete
  16. Good work! I always like to leave comments whenever I see something unusual or impressive. I think we must appreciate those who do something especial.
    Clipping Path service

    ReplyDelete

s;o