The fat-like cadherin CDH-4 acts cell-non-autonomously in anterior–posterior neuroblast migration

Abstract

Directed migration of neurons is critical in the normal and pathological development of the brain and central nervous system. In C. elegans, the bilateral Q neuroblasts, QR on the right and QL on the left, migrate anteriorly and posteriorly, respectively. Initial protrusion and migration of the Q neuroblasts is autonomously controlled by the transmembrane proteins UNC-40/DCC, PTP-3/LAR, and MIG-21. As QL migrates posteriorly, it encounters and EGL-20/Wnt signal that induces MAB-5/Hox expression that drives QL descendant posterior migration. QR migrates anteriorly away from EGL-20/Wnt and does not activate MAB-5/Hox, resulting in anterior QR descendant migration. A forward genetic screen for new mutations affecting initial Q migrations identified alleles of cdh-4, which caused defects in both QL and QR directional migration similar to unc-40, ptp-3, and mig-21. Previous studies showed that in QL, PTP-3/LAR and MIG-21 act in a pathway in parallel to UNC-40/DCC to drive posterior QL migration. Here we show genetic evidence that CDH-4 acts in the PTP-3/MIG-21 pathway in parallel to UNC-40/DCC to direct posterior QL migration. In QR, the PTP-3/MIG-21 and UNC-40/DCC pathways mutually inhibit each other, allowing anterior QR migration. We report here that CDH-4 acts in both the PTP-3/MIG-21 and UNC-40/DCC pathways in mutual inhibition in QR, and that CDH-4 acts cell-non-autonomously. Interaction of CDH-4 with UNC-40/DCC in QR but not QL represents an inherent left-right asymmetry in the Q cells, the nature of which is not understood. We conclude that CDH-4 might act as a permissive signal for each Q neuroblast to respond differently to anterior-posterior guidance information based upon inherent left-right asymmetries in the Q neuroblasts.

The Caenorhabditis elegans NF2/Merlin Molecule NFM-1 Nonautonomously Regulates Neuroblast Migration and Interacts Genetically with the Guidance Cue SLT-1/Slit

“…Although numerous molecules have been identified that act in the Q cells to promote migration, such as the transmembrane receptors UNC-40/DCC, PTP-3/ LAR, and MIG-13 (Sundararajan and Lundquist 2012;Wang et al 2013;Sundararajan et al 2015), fewer have been identified that act outside the Q cells to control their migration. Of the nonautonomous genes that have been implicated in Q-descendant migration, most are secreted molecules such as Wnts (Hunter et al 1999;Whangbo and Kenyon 1999;Korswagen 2002;Pan et al 2006) and SPON-1/F-spondin (Josephson et al 2016b), although the Fat-like cadherin CDH-4 has been demonstrated to nonautonomously affect Q-cell migration (Sundararajan et al 2014).…”

“…Mosaic analysis was conducted as previously dscribed (Chapman et al 2008;Sundararajan et al 2014) and involved generating a rescuing extrachromosomal array carrying nfm-1(+), and an independent marker of AQR and PQR position. The positions of AQR and PQR were determined in mosaics in which the rescuing extrachromosomal array was lost in AQR and/or PQR.…”

“…In C. elegans, extrachromosomal arrays are not stably inherited mitotically and can be lost during cell divisions, creating genetically mosaic animals. We used an established strategy to score mosaic animals that had lost an nfm-1(+) rescuing transgene in AQR or PQR lineage (see Materials and Methods and Chapman et al 2008;Sundararajan et al 2014). This strategy uses a stable Pgcy-32::cfp integrated transgene to visualize AQR and PQR in all animals, and an unstable array carrying the rescuing nfm-1::gfp fosmid and Pgcy-32::yfp, which we refer to as nfm-1(+).…”

“…Initial Q migrations are controlled autonomously by the receptor molecules UNC-40/DCC and PTP-3/LAR (Honigberg and Kenyon 2000;Sundararajan and Lundquist 2012) and nonautonomously by the Fat-like cadherin CDH-4 (Sundararajan et al 2014). Later Q-descendant migrations are controlled by Wnt signaling Zinovyeva and Forrester 2005;Zinovyeva et al 2008;Harterink et al 2011), which appears to not be involved in initial migration (Josephson et al 2016a), and by the transmembrane receptor MIG-13 in parallel with SDN-1/Syndecan (Wang et al 2013;Sundararajan et al 2015).…”

Fat-like cadherins in cell migration—leading from both the front and the back

“…Notably, work in C. elegans has shown that the Fat-like cadherin CDH-4 also appears to function in a signaling relationship with Lar to guide the migration of Q neuroblasts, with Lar (also known as PTP-3) acting cell-autonomously within the neuroblast and CDH-4 acting non-cell-autonomously in another tissue [33–35]. Thus, signaling between a Fat-like cadherin and Lar may be a widely used mechanism to direct cell migratory behavior.…”