The Flamingo ortholog FMI-1 controls pioneer-dependent navigation of follower axons inC. elegans

Abstract

SUMMARYDevelopment of a functional neuronal network during embryogenesis begins with pioneer axons creating a scaffold along which later-outgrowing axons extend. The molecular mechanism used by these follower axons to navigate along pre-existing axons remains poorly understood. We isolated loss-of-function alleles of fmi-1, which caused strong axon navigation defects of pioneer and follower axons in the ventral nerve cord (VNC) of C. elegans. Notably follower axons, which exclusively depend on pioneer axons for correct navigation, frequently separated from the pioneer. fmi-1 is the sole C. elegans ortholog of Drosophila flamingo and vertebrate Celsr genes, and this phenotype defines a new role for this important molecule in follower axon navigation. FMI-1 has a unique and strikingly conserved structure with cadherin and C-terminal G-protein coupled receptor domains and could mediate cell-cell adhesion and signaling functions. We found that follower axon navigation depended on the extracellular but not on the intracellular domain, suggesting that FMI-1 mediates primarily adhesion between pioneer and follower axons. By contrast, pioneer axon navigation required the intracellular domain, suggesting that FMI-1 acts as receptor transducing a signal in this case. Our findings indicate that FMI-1 is a cell-type dependent axon guidance factor with different domain requirements for its different functions in pioneers and followers.

Pioneer Axon Navigation Is Controlled by AEX-3, a Guanine Nucleotide Exchange Factor for RAB-3 in Caenorhabditis elegans

“…For example, we found no correlation between AVK and AVG defects, indicating that AVK defects are not secondary consequences of AVG defects and that AVK navigation is independent of AVG. This is consistent with earlier studies, where defects in AVK axon navigation in the left axon tract were also independent of pioneer defects (Steimel et al 2010;Unsoeld et al 2012). The idea that aex-3 defects are not limited to the VNC pioneer is strengthened by the observation of synergistic effects in aex-3; nid-1 double mutants in commissural navigation, which is completely independent of AVG navigation.…”

Shear Stress–Dependent Downregulation of the Adhesion-G Protein–Coupled Receptor CD97 on Circulating Leukocytes upon Contact with Its Ligand CD55

“…Intriguingly, all bilateral frontoparietal polymicrogyria-associated missense mutations identified to date are located at the extracellular region of GPR56 (46). Other examples of aGPCRs with a role in cell adhesion are Flamingo and Latrophilin, which coordinate cell orientation and tissue polarity in Drosophila melanogaster and Caenorhabditis elegans, respectively (48)(49)(50)(51). The picture that arises from these studies is that aGPCRs facilitate the proper positioning of developing and motile cells in various organ systems via their extracellular modules.…”

International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G Protein–Coupled Receptors

“…The C. elegans ADGRC (CELSR) homolog FMI-1 appears to be involved in the navigation and shaping of neuronal processes during the development of GABAergic neurons (Steimel et al, 2010;Najarro et al, 2012;Huarcaya Najarro and Ackley, 2013). The instructive effects by a pioneer axon on follower axon movements were shown to rely on the ECD but not the 7TM nor ICD of FMI-1, indicating that the adhesion and/or trans signaling events figure prominently in this function (Steimel et al, 2010). Moreover, ADGRG1 (GPR56) inhibits migration of neural progenitors through coordinated action with a 3 b 1 integrin (Iguchi et al, 2008;Luo et al, 2011;Jeong et al, 2013 Cork et al, 2012).…”

“…ADGRC subfamily members (Flamingo/Starry night/ CELSRs) influence neural tube closure, the subcellular distribution of ependymal cilia, axon guidance, dendritic morphogenesis, and neuronal migration (Steimel et al, 2010;Berger-Muller and Suzuki, 2011;Boutin et al, 2012;Chai et al, 2014). ADGRC1 (CELSR1) facilitates neural tube closure via core-PCP signaling (Nishimura et al, 2012).…”