A Novel Nondevelopmental Role of the SAX-7/L1CAM Cell Adhesion Molecule in Synaptic Regulation in<i>Caenorhabditis elegans</i>

Opperman, Karla J.; Moseley-Alldredge, Melinda; Yochem, John; Bell, Leslie; Kanayinkal, Tony; Chen, Lihsia

doi:10.1534/genetics.114.169581

Cited by 14 publications

(15 citation statements)

References 74 publications

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“…In addition to non-neuronal functions (Grana et al, 2010; Jafari et al, 2010; Lynch et al, 2012), sax-7 /L1CAM is important for development and maintenance of different aspects of the nervous system (Sasakura et al, 2005; Wang et al, 2005; Pocock et al, 2008; Dong et al, 2013; Salzberg et al, 2013; Opperman et al, 2015). Interestingly, distinct domains of the protein are necessary for different processes.…”

Section: Discussionmentioning

confidence: 99%

The Adhesion Molecule KAL-1/anosmin-1 Regulates Neurite Branching through a SAX-7/L1CAM–EGL-15/FGFR Receptor Complex

et al. 2015

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Summary Neurite branching is essential for correct assembly of neural circuits, yet remains a poorly understood process. For example, the neural cell adhesion molecule KAL-1/anosmin-1, which is mutated in Kallmann Syndrome regulates neurite branching through mechanisms largely unknown. Here we show that KAL-1/anosmin-1 mediates neurite branching as an autocrine co-factor with EGL-17/FGF through a receptor complex consisting of the conserved cell adhesion molecule SAX-7/L1CAM and the fibroblast growth factor receptor EGL-15/FGFR. This protein complex, which appears conserved in humans, requires the immunoglobulin (Ig) domains of SAX-7/L1CAM and the FN(III) domains of KAL-1/anosmin-1 for formation in vitro as well as function in vivo. The kinase domain of the EGL-15/FGFR is required for branching, and genetic evidence suggests that ras-mediated signaling downstream of EGL-15/FGFR is necessary to effect branching. Our studies establish a molecular pathway that regulates neurite branching during development of the nervous system.

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Section: Discussionmentioning

confidence: 99%

The Adhesion Molecule KAL-1/anosmin-1 Regulates Neurite Branching through a SAX-7/L1CAM–EGL-15/FGFR Receptor Complex

et al. 2015

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“…Olfactory bulbs were not analyzed in this study but defects within them could in theory impact the behavior of the mice in the elevated plus maze. Second, loss of L1cam in new immature neurons could non-autonomously affect synaptic transmission of existing mature neurons, as described in certain C. elegans neurons ( Opperman et al, 2015 ), thus indirectly impacting behavior. Finally, the observed behavioral difference could alternatively be due to disruption of amygdala neurons since these also express DCX (Jhaveri et al, 2018).…”

Section: Discussionmentioning

confidence: 92%

L1cam curbs the differentiation of adult-born hippocampal neurons

2020

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L1 is an immunoglobulin domain (Ig)-containing protein essential for a wide range of neurodevelopmental processes highly conserved across species from worms to humans. L1 can act as a cell adhesion molecule by binding to other Ig-containing proteins or as a ligand for certain tyrosine kinase receptors such as FGFRs and TRKs, which are required not only during neurodevelopment but also in hippocampal neurogenesis. Yet, the role of L1 itself in adult hippocampal neurogenesis remains unaddressed. Here, we used several Cre-driver lines in mice to conditionally delete a floxed allele of L1cam at different points along the differentiation lineage of new neurons and in surrounding neurons in the adult dentate gyrus of the hippocampus. We found that L1cam deletion in stem/progenitor cells increased: 1) the differentiation of progenitors into new neurons, 2) the complexity of dendritic arbors in immature neurons, and 3) anxiety-related behavior. In addition, deletion of L1cam in neurons leads to an earlier age-related decline in hippocampal neurogenesis. These data suggest that L1 is not only important for normal nervous system development, but also for maintaining certain neural processes in adulthood.

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“…In C. elegans, SAX-7 affects the development and maintenance of many aspects of nervous system organization, including axon guidance, synapse function, dendrite fasciculation, axon and neuronal cell body positioning, and the spatial patterning of branched dendrite arbors (Zallen et al, 1999;Kim and Li, 2004;Sasakura et al, 2005;Bénard et al, 2012;Dong et al, 2013;Salzberg et al, 2013;Opperman et al, 2015;Yip and Heiman, 2018;Chen et al, 2019;Ramirez-Suarez et al, 2019). In these contexts, SAX-7 has been shown to physically interact with UNC-44/ankyrin, STN-2/γ-syntrophin, the transmembrane protein DMA-1, and the contactin RIG-6 (Zhou et al, 2008;Liu and Shen, 2011;Dong et al, 2013;Salzberg et al, 2013;Kim and Emmons, 2017).…”

Section: Sax-7mentioning

confidence: 99%

Dendrites with specialized glial attachments develop by retrograde extension using SAX-7 and GRDN-1

Cebul

McLachlan

Heiman

2019

Preprint

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Dendrites develop elaborate morphologies in concert with surrounding glia, but the molecules that coordinate dendrite and glial morphogenesis are mostly unknown. C. elegans offers a powerful model for identifying such factors. Previous work in this system examined dendrites and glia that develop within epithelia, similar to mammalian sense organs. Here, we focus on the neurons BAG and URX, which are not part of an epithelium but instead form membranous attachments to a single glial cell at the nose, reminiscent of dendrite-glia contacts in the mammalian brain. We show that these dendrites develop by retrograde extension, in which the nascent dendrite endings anchor to the presumptive nose and then extend by stretch during embryo elongation. Using forward genetic screens, we find that dendrite development requires the adhesion protein SAX-7/L1CAM and the cytoplasmic protein GRDN-1/CCDC88C to anchor dendrite endings at the nose. SAX-7 acts in neurons and glia, while GRDN-1 acts in glia to nonautonomously promote dendrite extension. Thus, this work shows how glial factors can help to shape dendrites, and identifies a novel molecular mechanism for dendrite growth by retrograde extension.C. elegans offers several advantages. Each cell can be uniquely identified and has a remarkably stereotyped shape and set of cell-cell contacts; neuron-and glia-specific promoters allow the targeted expression of transgenes in single cells to visualize and manipulate specific neuron-glia contacts in intact living animals; and its powerful genetics permit unbiased screens to identify factors that control neuron-glia interactions. Additionally, C. elegans glia share a number of important features with mammalian glia (Mizeracka and Heiman, 2015). This system Retrograde extension by SAX-7 and GRDN-1 4 thus offers a powerful genetic model for dissecting dendrite-glia contacts. Here, we turned our attention to a previously overlooked class of dendrite-glia contacts whose elaborate, tightly apposed membranous structures are reminiscent of the highly coordinated membranous contacts found between astrocytes and dendritic spines at mammalian synapses.Using super-resolution microscopy, we find that the dendrites of two neuron types, URX and BAG, form specialized attachments with a single glial partner. Using forward genetics, we identify two conserved molecules, SAX-7 and GRDN-1, that are required for the development of these dendrites. SAX-7 is a homolog of the mammalian neuron-glia adhesion molecule L1CAM, and GRDN-1 is a homolog of proteins involved in cell polarity and cytoskeleton organization.Each of these homologs is expressed in the mammalian brain and causes developmental brain disorders when disrupted (Jouet et al., 1994;Vits et al., 1994; Ekici et al., 2010). Using embryonic time-course imaging, we find that URX and BAG dendrites develop by retrograde extension, a type of outgrowth in which the dendrites anchor to their targets and then extend by stretch. SAX-7 and GRDN-1 help to anchor dendrite endings at the nose during embryo elong...

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A Novel Nondevelopmental Role of the SAX-7/L1CAM Cell Adhesion Molecule in Synaptic Regulation inCaenorhabditis elegans

Cited by 14 publications

References 74 publications

The Adhesion Molecule KAL-1/anosmin-1 Regulates Neurite Branching through a SAX-7/L1CAM–EGL-15/FGFR Receptor Complex

The Adhesion Molecule KAL-1/anosmin-1 Regulates Neurite Branching through a SAX-7/L1CAM–EGL-15/FGFR Receptor Complex

L1cam curbs the differentiation of adult-born hippocampal neurons

Dendrites with specialized glial attachments develop by retrograde extension using SAX-7 and GRDN-1

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