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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    ABSTRACT: Neural cell adhesion molecule close homolog of L1 (CHL1) is a regulator of topographic targeting of thalamic axons to the somatosensory cortex (S1) but little is known about its cooperation with other L1 class molecules. To investigate this, CHL1(-/-)/L1(-/y) double mutant mice were generated and analyzed for thalamocortical axon topography. Double mutants exhibited a striking posterior shift of axons from motor thalamic nuclei to the visual cortex (V1), which was not observed in single mutants. In wild-type (WT) embryos, L1 and CHL1 were coexpressed in the dorsal thalamus (DT) and on fibers along the thalamocortical projection in the ventral telencephalon and cortex. L1 and CHL1 colocalized on growth cones and neurites of cortical and thalamic neurons in culture. Growth cone collapse assays with WT and mutant neurons demonstrated a requirement for L1 and CHL1 in repellent responses to EphrinA5, a guidance factor for thalamic axons. L1 coimmunoprecipitated with the principal EphrinA5 receptors expressed in the DT (EphA3, EphA4, and EphA7), whereas CHL1 associated selectively with EphA7. These results implicate a novel mechanism in which L1 and CHL1 interact with individual EphA receptors and cooperate to guide subpopulations of thalamic axons to distinct neocortical areas essential for thalamocortical connectivity.
    Cerebral Cortex 02/2011; 21(2):401-12. DOI:10.1093/cercor/bhq115 · 8.67 Impact Factor
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    • "As transmembrane proteins, L1CAMs have been shown to form cell– cell and cell–ECM adhesion via diverse extracellular interactions as well as associate with the membrane actin cytoskeleton by binding cytoskeletal linkers, such as ankyrin. This cytoskeletal anchorage via ankyrin has been shown to be important for L1CAM function (Needham et al., 2001; Buhusi et al., 2008). Ankyrin interaction is similarly important for SAX-7 function (Zhou et al., 2008). "
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    ABSTRACT: The dystrophin protein complex (DPC), composed of dystrophin and associated proteins, is essential for maintaining muscle membrane integrity. The link between mutations in dystrophin and the devastating muscle failure of Duchenne's muscular dystrophy (DMD) has been well established. Less well appreciated are the accompanying cognitive impairment and neuropsychiatric disorders also presented in many DMD patients, which suggest a wider role for dystrophin in membrane-cytoskeleton function. This study provides genetic evidence of a novel role for DYS-1/dystrophin in maintaining neural organization in Caenorhabditis elegans. This neuronal function is distinct from the established role of DYS-1/dystrophin in maintaining muscle integrity and regulating locomotion. SAX-7, an L1 cell adhesion molecule (CAM) homologue, and STN-2/γ-syntrophin also function to maintain neural integrity in C. elegans. This study provides biochemical data that show that SAX-7 associates with DYS-1 in an STN-2/γ-syntrophin-dependent manner. These results reveal a recruitment of L1CAMs to the DPC to ensure neural integrity is maintained.
    The Journal of Cell Biology 01/2011; 192(2):349-63. DOI:10.1083/jcb.201006109 · 9.69 Impact Factor
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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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    ABSTRACT: Topographic maps are a two-dimensional representation of one neural structure within another and serve as the main strategy to organize sensory information. The retina's projection via axons of retinal ganglion cells to midbrain visual centers, the optic tectum/superior colliculus, is the leading model to elucidate mechanisms of topographic map formation. Each axis of the retina is mapped independently using different mechanisms and sets of axon guidance molecules expressed in gradients to achieve the goal of representing a point in the retina onto a point within the target. An axon's termination along the temporal-nasal mapping axis is determined by opposing gradients of EphAs and ephrin-As that act through their forward and reverse signaling, respectively, within the projecting axons, each of which inhibits interstitial branching, cooperating with a branch-promoting activity, to generate topographic specific branching along the shaft of the parent axons that overshoot their correct termination zone along the anterior-posterior axis of the target. The dorsal-ventral termination position is then determined using a gradient of ephrin-B that can act as a repellent or attractant depending on the ephrin-B concentration relative to EphB levels on the interstitial branches to guide them along the medial-lateral axis of the target to their correct termination zone, where they arborize. In both cases, axon-axon competition results in axon mapping based on relative rather than absolute levels of repellent or attractant activity. The map is subsequently refined through large-scale pruning driven in large part by patterned retinal activity.
    Cold Spring Harbor perspectives in biology 09/2010; 2(11):a001768. DOI:10.1101/cshperspect.a001768 · 8.23 Impact Factor
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