Probing the brain toolkit, one disorder at a time

A short review in Science by Greg Miller discusses genetic correlates of dyslexia.

In one new study, a collaboration of 20 researchers led by Haiying Meng and Jeffrey Gruen of Yale University School of Medicine homed in on a region of chromosome 6 that had been fingered previously. Using DNA from 536 people with a dyslexic in their families, the researchers tracked 147 single-nucleotide polymorphisms (SNPs), spots where the genetic code differs by one letter among individuals. Searching for SNPs that tend to have one "spelling" in people with reading impairments and another spelling in normal readers, the researchers found a disproportionate number of such SNPs in a gene called DCDC2. They also found that about 17% of dyslexics were missing a short stretch of DNA within DCDC2. Everyone who had this deletion had dyslexia, Gruen says.

Am I the only one who finds it particularly perverse to refer to SNPs as having "another spelling" in people with reading impairments?

In any event, two of the genes identified here -- DCDC2 and ROBO1 (OMIM) -- both have functions in neuron migration and connections in animal models.

ROBO1 is especially interesting, because it appears to be an inhibitor of neural connections across the midline: </p>

Axonal growth cones that cross the nervous system midline change their responsiveness to midline guidance cues: they become repelled by the repellent Slit (603746) and simultaneously lose responsiveness to the attractant netrin (601614). These mutually reinforcing changes help to expel growth cones from the midline by making a once-attractive environment appear repulsive. Stein and Tessier-Lavigne (2001) provided evidence that these 2 changes are causally linked: in the growth cones of embryonic Xenopus spinal axons, activation of the Slit receptor Robo silences the attractive effect of netrin-1, but not its growth-stimulatory effect, through direct binding of the cytoplasmic domain of Robo to that of the netrin receptor DCC (120470). Biologically, this hierarchical silencing mechanism helps to prevent a tug-of-war between attractive and repulsive signals in the growth cone that might cause confusion. Molecularly, silencing is enabled by a modular and interlocking design of the cytoplasmic domains of these potentially antagonistic receptors that predetermines the outcome of their simultaneous activation.
Using a variety of mammalian, avian, and Drosophila constructs and cells, Rhee et al. (2002) showed that Robo, activated by Slit (see 603742), disrupted cell adhesion and neurite outgrowth mediated by N-cadherin (114020). Robo activation was accompanied by tyrosine phosphorylation of beta-catenin (116806) and the loss of beta-catenin from N-cadherin complexes. The result was the formation of a complex between Robo and N-cadherin, uncoupling N-cadherin from its association with the cytoskeleton. The C terminus of Robo mediated these effects. Rhee et al. (2002) concluded that a repulsive cue could be directly converted into decreased traction between the growth cone and the substrate (OMIM).

In other words, ROBO1 may help mediate the connection of the two hemispheres. The functional link to dyslexia is not yet clear, but one might speculate about a possible disruption (or even an undesirable increase) of across-brain communication and integration of sensory or cognitive information.

A third gene, KIAA0319, may also be involved in brain development.

One may imagine a system of toolkit genes, activated differently in different parts of the developing cortex during early embryonic development. Later, the gene products regulate the responsiveness of different neurons to growth activators and inhibitors. This system results in the shape of the brain -- where the neurons are, and where they aren't. It can draw the migration of some neurons across cortical layers, and sketch their axons across the brain.

It is therefore interesting that we are beginning to connect observable variation in brain function to some of these activators and inhibitors -- the last links in the chain of brain development. In contrast, toolkit genes are essential to tissue differentiation and the spatial determination of body parts. Elsewhere in the body, alterations to toolkit genes may result in segmental duplications, agenesis of body parts (such as limbs, fingers, or organs) and other gross anatomical abnormalities.

We have developed a lot of information about toolkit genes in the body (the Hox clusters are the best-known example). But so far we know less about the genes that influence the early development and differentiation of the brain. Perhaps the microcephaly-related genes are part of this neurodevelopmental toolkit. Perhaps most of the toolkit effects are yet earlier in development, and mutations result in nonviability. Or perhaps there is a large set of low-incidence brain-region-specific developmental disorders that have yet to be systematized.

References:

Miller G. 2005. Genes that guide brain development linked to dyslexia. Science 310:759. Full text (subscription)

Rhee, J.; Mahfooz, N. S.; Arregui, C.; Lilien, J.; Balsamo, J.; VanBerkum, M. F. A. 2002. Activation of the repulsive receptor roundabout inhibits N-cadherin-mediated cell adhesion. Nature Cell Biol 4: 798-805. PubMed

Stein, E.; Tessier-Lavigne, M. 2001. Hierarchical organization of guidance receptors: silencing of netrin attraction by Slit through a Robo/DCC receptor complex. Science 291: 1928-1938. PubMed