Human Genetic Disorders of Axon Guidance

Department of Neurology, FM Kirby Neurobiology Center, Program in Genomics, Children's Hospital Boston, Massachusetts 02115-5737, USA.
Cold Spring Harbor perspectives in biology (Impact Factor: 8.68). 03/2010; 2(3):a001784. DOI: 10.1101/cshperspect.a001784
Source: PubMed


This article reviews symptoms and signs of aberrant axon connectivity in humans, and summarizes major human genetic disorders that result, or have been proposed to result, from defective axon guidance. These include corpus callosum agenesis, L1 syndrome, Joubert syndrome and related disorders, horizontal gaze palsy with progressive scoliosis, Kallmann syndrome, albinism, congenital fibrosis of the extraocular muscles type 1, Duane retraction syndrome, and pontine tegmental cap dysplasia. Genes mutated in these disorders can encode axon growth cone ligands and receptors, downstream signaling molecules, and axon transport motors, as well as proteins without currently recognized roles in axon guidance. Advances in neuroimaging and genetic techniques have the potential to rapidly expand this field, and it is feasible that axon guidance disorders will soon be recognized as a new and significant category of human neurodevelopmental disorders.

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    • "The cortical innervation defects that occur in the absence of Slit/Robo signaling in mice resemble defects present in mouse models of Down syndrome [2], [3]. Moreover, defects in Slit/Robo signaling disrupt commissural axon crossing in the hindbrain in horizontal gaze palsy with progressive scoliosis [4], [5]. The Slit/Robo signaling pathway is also associated with early infantile epileptic encephalopathy [6] and autism [7]. "
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    ABSTRACT: The Slit/Robo axon guidance families play a vital role in the formation of neural circuitry within select regions of the developing mouse nervous system. Typically Slits signal through the Robo receptors, however they also have Robo-independent functions. The novel Slit receptor Eva-1, recently discovered in C. elegans, and the human orthologue of which is located in the Down syndrome critical region on chromosome 21, could account for some of these Robo independent functions as well as provide selectivity to Robo-mediated axon responses to Slit. Here we investigate the expression of the mammalian orthologue EVA1C in regions of the developing mouse nervous system which have been shown to exhibit Robo-dependent and -independent responses to Slit. We report that EVA1C is expressed by axons contributing to commissures, tracts and nerve pathways of the developing spinal cord and forebrain. Furthermore it is expressed by axons that display both Robo-dependent and -independent functions of Slit, supporting a role for EVA1C in Slit/Robo mediated neural circuit formation in the developing nervous system.
    PLoS ONE 09/2013; 8(9):e74115. DOI:10.1371/journal.pone.0074115 · 3.23 Impact Factor
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    • "Vertebrate Teneurins have been suggested to be related to mental diseases and our discovery of Ten-a function in Drosophila brain development seems to support the hypothesis. Neuroglian (Nrg), whose vertebrate homologue L1-CAM has been implicated in neurological disorders [38], [39], is also required for development of normal brain morphology in Drosophila [40], [41]. Considering that both Nrg and Ten-a are type-II transmembrane proteins with extracellular EGF repeats and also function in glial cells for brain development [40], it is possible that Teneurins in vertebrates also affect brain development, and probably synapse formation, as vertebrate Nrg does. "
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    ABSTRACT: The central complex of Drosophila melanogaster plays important functions in various behaviors, such as visual and olfactory memory, visual orientation, sleep, and movement control. However little is known about the genes regulating the development of the central complex. Here we report that a mutant gene affecting central complex morphology, cbd (central brain defect), was mapped to ten-a, a type II trans-membrane protein coding gene. Down-regulation of ten-a in pan-neural cells contributed to abnormal morphology of central complex. Over-expression of ten-a by C767-Gal4 was able to partially restore the abnormal central complex morphology in the cbd mutant. Tracking the development of FB primordia revealed that C767-Gal4 labeled interhemispheric junction that separated fan-shaped body precursors at larval stage withdrew to allow the fusion of the precursors. While the C767-Gal4 labeled structure did not withdraw properly and detached from FB primordia, the two fan-shaped body precursors failed to fuse in the cbd mutant. We propose that the withdrawal of C767-Gal4 labeled structure is related to the formation of the fan-shaped body. Our result revealed the function of ten-a in central brain development, and possible cellular mechanism underlying Drosophila fan-shaped body formation.
    PLoS ONE 02/2013; 8(2):e57129. DOI:10.1371/journal.pone.0057129 · 3.23 Impact Factor
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    • "The detailed and robust in utero visualization of the Probst bundle by in vivo tractography further confirms that this technique is clinically feasible in the early diagnostic assessment of the growing group of 'disorders of axon guidance' (Engle, 2010; Tischfield et al., 2010). It substantially widens the diagnostic capabilities of prenatal MRI, allowing for a more detailed analysis of anatomically abnormally configured or positioned white matter pathways. "
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    ABSTRACT: Complete or partial agenesis of the corpus callosum are rather common developmental abnormalities, resulting in a wide spectrum of clinical neurodevelopmental deficits. Currently, a significant number of these cases are detected by prenatal sonography during second trimester screening examinations. However, major uncertainties about a detailed morphological diagnosis and the clinical significance do not allow accurate prenatal counselling. Here, we were able to demonstrate the 3D connectivity of aberrant commissural tracts in 16 cases with complete and four cases with partial callosal agenesis using the foetal magnetic resonance imaging techniques of diffusion tensor imaging and tractography in utero and in vivo between gestational weeks 20 and 37. The 'misguided' pre-myelinated callosal axons that represent the bundle of Probst were non-invasively visualized, and they showed a degree of structural integrity similar to that of the callosal pathways of age-matched foetuses without cerebral pathologies. In two foetuses, we were able to prove, by post-mortem histology, that diffusion tensor imaging allows the depiction of the bundle of Probst, even during early stages of pre-myelination at 20 and 22 gestational weeks. In cases with partial callosal agenesis, an aberrant sigmoid-shaped bundle was prenatally depicted, confirming the findings of heterotopic interhemispheric connectivity in adults with partial callosal agenesis. In addition to the corpus callosum, other white matter pathways were also involved, including somatosensory and motor pathways that showed significantly higher fractional anisotropy values in cases with callosal agenesis compared with control subjects. A detailed prenatal assessment of abnormal white matter connectivity in cases of midline anomalies will help to explain and understand the clinical heterogeneity in these cases, taking future foetal neurological counselling strategies to a new level.
    Brain 01/2013; 136(Pt 1):168-79. DOI:10.1093/brain/aws332 · 9.20 Impact Factor
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