L1 Interaction with Ankyrin Regulates Mediolateral Topography in the Retinocollicular Projection
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.
Available from: Mona Buhusi
- "In each bin, the total number of labeled RGC axons and branches was measured, and medial or lateral branch orientation of each branch was scored (Fig. 5A–B). A directional coefficient (DC) was calculated by subtracting the number of laterally oriented branches from medially oriented branches, and dividing the result by the total number of branches, as previously described , , . A positive DC indicated that there were more medial than lateral branches; a negative DC indicated more lateral than medial branches. "
[Show abstract] [Hide abstract]
ABSTRACT: NrCAM (Neuron-glial related cell adhesion molecule), a member of the L1 family of cell adhesion molecules, reversibly binds ankyrin and regulates axon growth, but it has not been studied for a role in retinotopic mapping. During development of retino-collicular topography, NrCAM was expressed uniformly in retinal ganglion cells (RGCs) along both mediolateral and anteroposterior retinal axes, and was localized on RGC axons within the optic tract and superior colliculus (SC). Anterograde tracing of RGC axons in NrCAM null mutant mice at P10, when the map resembles its mature form, revealed laterally displaced ectopic termination zones (eTZs) of axons from the temporal retina, indicating defective mediolateral topography, which is governed by ephrinB/EphBs. Axon tracing at P2 revealed that interstitial branch orientation of ventral-temporal RGC axons in NrCAM null mice was compromised in the medial direction, likely accounting for displacement of eTZs. A similar retinocollicular targeting defect in EphB mutant mice suggested that NrCAM and EphB interact to regulate mediolateral retino-collicular targeting. We found that EphB2 tyrosine kinase but not an EphB2 kinase dead mutant, phosphorylated NrCAM at a conserved tyrosine residue in the FIGQY ankyrin binding motif, perturbing ankyrin recruitment in NrCAM transfected HEK293 cells. Furthermore, the phosphorylation of NrCAM at FIGQY in SC was decreased in EphB1/3 and EphB1/2/3 null mice compared to WT, while phospho-FIGQY of NrCAM in SC was increased in EphB2 constitutively active (F620D/F620D) mice. These results demonstrate that NrCAM contributes to mediolateral retinocollicular axon targeting by regulating RGC branch orientation through a likely mechanism in which ephrinB/EphB phosphorylates NrCAM to modulate linkage to the actin cytoskeleton.
PLoS ONE 09/2013; 8(9):e73000. DOI:10.1371/journal.pone.0073000 · 3.23 Impact Factor
Available from: Udo Bartsch
- "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). "
[Show abstract] [Hide abstract]
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
Available from: PubMed Central
- "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). "
[Show abstract] [Hide abstract]
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 · 9.83 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.