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L1 interaction with ankyrin regulates mediolateral topography in the retinocollicular projection

Department of Biochemistry, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.75). 02/2008; 28(1):177-88. DOI: 10.1523/JNEUROSCI.3573-07.2008
Source: PubMed

ABSTRACT Dynamic modulation of adhesion provided by anchorage of axonal receptors with the cytoskeleton contributes to attractant or repellent responses that guide axons to topographic targets in the brain. The neural cell adhesion molecule L1 engages the spectrin-actin cytoskeleton through reversible linkage of its cytoplasmic domain to ankyrin. To investigate a role for L1 association with the cytoskeleton in topographic guidance of retinal axons to the superior colliculus, a novel mouse strain was generated by genetic knock-in that expresses an L1 point mutation (Tyr1229His) abolishing ankyrin binding. Axon tracing revealed a striking mistargeting of mutant ganglion cell axons from the ventral retina, which express high levels of ephrinB receptors, to abnormally lateral sites in the contralateral superior colliculus, where they formed multiple ectopic arborizations. These axons were compromised in extending interstitial branches in the medial direction, a normal response to the high medial to low lateral SC gradient of ephrinB1. Furthermore, ventral but not dorsal L1(Y1229H) retinal cells were impaired for ephrinB1-stimulated adhesion through beta1 integrins in culture. The retinocollicular phenotype of the L1(Tyr1229His) mutant provides the first evidence that L1 regulates topographic mapping of retinal axons through adhesion mediated by linkage to the actin cytoskeleton and functional interaction with the ephrinB/EphB targeting system.

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    • "L1 mutations at human chromosomal locus Xq28 result in a pleiotropic syndrome of mental retardation (Kenwrick et al. 2000), and the human homolog of CHL1 at 3p26.1 (CALL) is implicated in the 3p-syndrome of low IQ and developmental delay (Frints et al. 2003). L1 null mutant mice display errors of axon guidance in the corticospinal tract (CST) (Dahme et al. 1997; Cohen et al. 1998), corpus callosum (Demyanenko et al. 1999), and retinocollicular projection (Demyanenko and Maness 2003; Buhusi et al. 2008), and they are learning impaired (Fransen et al. 1998). CHL1 null mutant mice show aberrant thalamocortical projections (Wright et al. 2007), abnormal positioning of cortical neurons (Demyanenko et al. 2004), deficits in cognitive processing of spatial information (Montag-Sallaz et al. 2002), attention, sensory gating (Pratte et al. 2003; Irintchev et al. 2004), and working memory (Kolata et al. 2008). "
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    • "Mice mutant for the homophilic cell adhesion molecule L1 have topographic mapping defects along both axes of the SC (Demyanenko and Maness 2003). Remarkably, mice with a Y1229H point mutation in the ankyrin binding region in L1 have mapping defects that are more constrained to just the D-V mapping axis (Buhusi et al. 2008). The mechanism for L1 in mapping is unclear, but has been speculated to influence ephrin-A function. "
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