Axon fasciculation defects and retinal dysplasias in mice lacking the immunoglobulin superfamily adhesion molecule BEN/ALCAM/SC1
ABSTRACT The immunoglobulin superfamily adhesion molecule BEN (other names include ALCAM, SC1, DM-GRASP, neurolin, and CD166) has been implicated in the control of numerous developmental and pathological processes, including the guidance of retinal and motor axons to their targets. To test hypotheses about BEN function, we disrupted its gene via homologous recombination and analyzed the resulting mutant mice. Mice lacking BEN are viable and fertile, and display no external morphological defects. Despite grossly normal trajectories, both motor and retinal ganglion cell axons fasciculated poorly and were occasionally misdirected. In addition, BEN mutant retinae exhibited evaginated or invaginated regions with photoreceptor ectopias that resembled the "retinal folds" observed in some human retinopathies. Together, these results demonstrate that BEN promotes fasciculation of multiple axonal populations and uncover an unexpected function for BEN in retinal histogenesis.
- SourceAvailable from: Marc Nicolas Faber
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- "ERK appears to be a key player in the regulation of ALCAM plasma membrane levels because this kinase, upon ALCAM activation, stimulates endocytosis as well as translation of ALCAM, with both processes acting in concert to ensure re-sensitization of ALCAM. The concomitant regulation of both processes by ERK might ensure the coordinated, swift control of ALCAM density in the plasma membrane and prevent fluctuations leading to fatal routing errors of the rapidly advancing growth cone, as have been observed upon transient, as well as permanent, abolishment of ALCAM in the developing retina (Avci et al., 2004; Weiner et al., 2004). Here, we show that the preference of RGC axons for ALCAMcontaining substrate lanes requires not only the presence of ALCAM protein but its continuous synthesis. "
ABSTRACT: ALCAM is a cell adhesion molecule that is present on extending axons and has been shown to be crucial for elongation and navigation of retinal ganglion cell (RGC) axons. In the present study, we show that ALCAM mRNA is present in axonal growth cones of RGCs in vivo and in vitro, and that translation of ALCAM occurs in RGC growth cones separated from their soma. This growth cone translation is regulated by the 3'-untranslated region (3'-UTR) of ALCAM and depends on the activity of the kinases ERK and TOR (target of rapamycin). We also investigated the impact of the growth cone translation of ALCAM on axonal functions. Growth cone translation of ALCAM is crucial for the enhanced elongation of axons extending in contact with ALCAM protein. The local translation of ALCAM in the growth cone is able to rapidly counterbalance experimentally induced ALCAM internalization, thereby contributing to the maintenance of constant ALCAM levels in the plasma membrane. Assays where RGC axons have the choice to grow on laminin or both ALCAM and laminin - as is the case in the developing retina - reveal that the axonal preference for ALCAM-containing lanes depends on translation of ALCAM in growth cones. Taken together, these results show for the first time that translation of a cell adhesion molecule in growth cones, as well as the impact of this local translation on the behavior of axon and growth cone.Journal of Cell Science 03/2012; 125(Pt 4):1003-14. DOI:10.1242/jcs.096149 · 5.33 Impact Factor
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- "Further work is still needed to determine the role of endogenous ALCAM in established neurotrophin-dependent processes using cells from ALCAM )/) mice as well as knockdown experiments. Based on the lack of overt developmental effects in ALCAM )/) mice (McKinnon et al. 2000; Weiner et al. 2004), a common occurrence in single "
ABSTRACT: Cell adhesion molecules of the immunoglobulin superfamily (IgCAMs) have been shown to modulate growth factor signaling and follow complex trafficking pathways in neurons. Similarly, several growth factors, including members of the neurotrophin family, undergo axonal retrograde transport that is required to elicit their full signaling potential in neurons. We sought to determine whether IgCAMs that enter the axonal retrograde transport route co-operate with neurotrophin signaling. We identified activated leukocyte cell adhesion molecule (ALCAM), a protein involved in axon pathfinding and development of the neuromuscular junction, to be associated with an axonal endocytic compartment that contains neurotrophins and their receptors. Although ALCAM enters carriers that are transported bidirectionally in motor neuron axons, it is predominantly co-transported with the neurotrophin receptor p75(NTR) toward the cell body. ALCAM was found to specifically potentiate nerve growth factor (NGF)-induced differentiation and signaling. The extracellular domain of ALCAM is both necessary and sufficient to potentiate NGF-induced neurite outgrowth, and its homodimerization is required for this novel role. Our findings indicate that ALCAM synergizes with NGF to induce neuronal differentiation, raising the possibility that it functions not only as an adhesion molecule but also in the modulation of growth factor signaling in the nervous system.Journal of Neurochemistry 01/2012; 121(4):575-86. DOI:10.1111/j.1471-4159.2012.07658.x · 4.24 Impact Factor
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- "In zebrafish, Alcama has been studied primarily for its role in neurogenesis (Diekmann and Stuermer, 2009; Fashena and Westerfield, 1999). Initially identified in chicken for its role in neurite extension (Burns et al., 1991), ALCAMA has now been shown to be involved in axonal pathfinding and axonal fasciculation (Diekmann and Stuermer, 2009; Weiner et al., 2004). Its non-neuronal roles include T-cell activation (Bowen et al., 2000; Fashena and Westerfield, 1999; Ofori-Acquah and King, 2008; Zimmerman et al., 2006), metastasis (Degen et al., 1998; Ofori-Acquah and King, 2008) and cell migration (Heffron and Golden, 2000). "
ABSTRACT: The zebrafish pharyngeal cartilage is derived from the pharyngeal apparatus, a vertebrate-specific structure derived from all three germ layers. Developmental aberrations of the pharyngeal apparatus lead to birth defects such as Treacher-Collins and DiGeorge syndromes. While interactions between endoderm and neural crest (NC) are known to be important for cartilage formation, the full complement of molecular players involved and their roles remain to be elucidated. Activated leukocyte cell adhesion molecule a (alcama), a member of the immunoglobulin (Ig) superfamily, is among the prominent markers of pharyngeal pouch endoderm, but to date no role has been assigned to this adhesion molecule in the development of the pharyngeal apparatus. Here we show that alcama plays a crucial, non-autonomous role in pharyngeal endoderm during zebrafish cartilage morphogenesis. alcama knockdown leads to defects in NC differentiation, without affecting NC specification or migration. These defects are reminiscent of the phenotypes observed when Endothelin 1 (Edn1) signaling, a key regulator of cartilage development is disrupted. Using gene expression analysis and rescue experiments we show that Alcama functions downstream of Edn1 signaling to regulate NC differentiation and cartilage morphogenesis. In addition, we also identify a role for neural adhesion molecule 1.1 (nadl1.1), a known interacting partner of Alcama expressed in neural crest, in NC differentiation. Our data shows that nadl1.1 is required for alcama rescue of NC differentiation in edn1(-/-) mutants and that Alcama interacts with Nadl1.1 during chondrogenesis. Collectively our results support a model by which Alcama on the endoderm interacts with Nadl1.1 on NC to mediate Edn1 signaling and NC differentiation during chondrogenesis.Developmental Biology 11/2010; 349(2):483-93. DOI:10.1016/j.ydbio.2010.11.006 · 3.64 Impact Factor