Recently several groups including ours have started to use

Recently, several groups, including ours, have started to use the C. elegans multi-dendritic PVD neurons as a model system to dissect the molecular mechanisms of dendrite development. During larval development, PVD elaborates complex and stereotyped dendritic arbors by sequentially adding primary (1°), secondary (2°), tertiary (3°) and quaternary (4°) EPZ031686 (Figures 1A and 1B) (Smith et al., 2010). The 3° branches grow precisely along the border of the outer body wall muscles, while the 4° branches innervate the narrow space between the epidermis and the body wall muscles, suggesting that the epidermal and muscle tissues provide guidance cues to regulate branch formation (Albeg et al., 2011). Indeed, a multi-protein ligand-receptor complex has been identified as an extrinsic cue in guiding PVD dendrite morphogenesis (Diaz-Balzac et al., 2016, Dong et al., 2013, Salzberg et al., 2013, Zou et al., 2016). This complex consists of the cell adhesion molecules SAX-7/L1CAM and MNR-1/Menorin, which are enriched in epidermis; the chemotaxin LECT-2/LECT2, which is secreted by the body wall muscle cells; and the cell adhesion receptor DMA-1, which is specifically expressed in PVD dendrites. SAX-7 forms a striped pattern on epidermis that correlates with the location of the 3° and 4° branches (Dong et al., 2013, Liang et al., 2015, Salzberg et al., 2013), whereas the epidermis-specific expression of MNR-1 specifies the attachment points for PVD dendrites (Dong et al., 2013, Salzberg et al., 2013). Both genetic and biochemical experiments support a model where the three ligand proteins from the epidermis/muscle cells, including SAX-7, MNR-1, and LECT-2, simultaneously bind to the extracellular domain of the dendrite-specific receptor DMA-1, leading to the formation of an inter-cellular complex that specifies the precise location of dendritic arborization (Diaz-Balzac et al., 2016, Liu and Shen, 2012, Zou et al., 2016). However, it remains unknown how this extrinsic cue is transmitted through DMA-1 to instruct intracellular signaling in the PVD neuron and, subsequently, drive dendrite branching. In addition to DMA-1, a dendrite-specific, claudin-like transmembrane protein, HPO-30, was also identified as an essential regulator of PVD dendritic branching (Smith et al., 2013). Loss of hpo-30 results in a severe defect in dendrite morphogenesis similar to the dma-1 mutants (Smith et al., 2013). Claudins are transmembrane proteins important for the establishment and function of tight junctions in mammals, through both cis and trans interactions (Krause et al., 2008). In addition to their major roles in tight-junction formation, claudins may play a role in mediating signaling. For example, Claudin-1 has been shown to act as a co-receptor for the hepatitis C virus during a late step of viral entry (Evans et al., 2007). It is not known how HPO-30 mediates signaling to control dendrite branching.
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Acknowledgments This work was supported by the Howard Hughes Medical Institute and the National Institute of Neurological Disorders and Stroke (1R01NS082208), National Natural Science Foundation of China (31571061), and the CAS/SAFEA International Partnership Program for Creative Research Teams to K.S., National Natural Science Foundation of China (31741056) to W.Z., the National Institute of Neurological Disorders and Stroke (1R01NS079611) to D.M.M., and start-up funds to B.C. from the Iowa State University and the Roy J. Carver Charitable Trust. Some strains were provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440), and the MITANI Lab through the National Bio-Resource Project of the MEXT, Japan. We thank Drs. Suhong Xu, Zhiping Wang, Erik Lundquist, Jeremy Nance, Jordan Ward, Bob Goldstein, Erik Jorgensen, Yuji Kohara, and Liqun Luo for kindly sharing equipment and/or reagents and Cen Gao for technique assistance.