Transmembrane Proteins UNC-40/DCC, PTP-3/LAR, and MIG-21 Control Anterior–Posterior Neuroblast Migration with Left–Right Functional Asymmetry in Caenorhabditis elegans

Abstract

Migration of neurons and neural crest cells is of central importance to the development of nervous systems. In Caenorhabditis elegans, the QL neuroblast on the left migrates posteriorly, and QR on the right migrates anteriorly, despite similar lineages and birth positions with regard to the left-right axis. Initial migration is independent of a Wnt signal that controls later anteriorposterior Q descendant migration. Previous studies showed that the transmembrane proteins UNC-40/DCC and MIG-21, a novel thrombospondin type I repeat containing protein, act redundantly in left-side QL posterior migration. Here we show that the LAR receptor protein tyrosine phosphatase PTP-3 acts with MIG-21 in parallel to UNC-40 in QL posterior migration. We also show that in right-side QR, the UNC-40 and PTP-3/MIG-21 pathways mutually inhibit each other's role in posterior migration, allowing anterior QR migration. Finally, we present evidence that these proteins act autonomously in the Q neuroblasts. These studies indicate an inherent left-right asymmetry in the Q neuroblasts with regard to UNC-40, PTP-3, and MIG-21 function that results in posterior vs. anterior migration.C ELL migration is a fundamental event in the development of nervous systems. In the vertebrate central nervous system, neurons and neuroblasts migrate radially to populate distinct layers in the cerebellar and cerebral cortices, and neural crest cells migrate along distinct paths in the vertebrate embryo to give rise to the peripheral nervous system. The Q neuroblasts in Caenorhabditis elegans are a useful model to study the migration of neuroblasts and neurons in the anterior-posterior axis. The Q neuroblasts are a bilaterally symmetric pair of cells in the posteriorlateral region of the animal, with QR on the right side and QL on the left side (Sulston and Horvitz 1977). The Q neuroblasts are born in embryogenesis and are the sisters of the V5 hypodermal seam cells. By 5 hr after hatching, QR has migrated anteriorly and divided over the V4 seam cell, and QL has migrated posteriorly and divided over the V5 seam cell (Honigberg and Kenyon 2000;Chapman et al. 2008;Dyer et al. 2010). The resulting Q cell descendants then undergo a pattern of migration, division, and programmed cell death resulting in three neurons each (AQR, SDQR, and AVM on the right from QR; and PQR, SDQL, and PVM on the left from QL) (Sulston and Horvitz 1977;Chalfie and Sulston 1981). The QR descendant AQR migrates the longest distance to a region near the anterior deirid ganglion in the head, and the QL descendant PQR migrates the longest distance posteriorly to the phasmid ganglion in the tail (Sulston and Horvitz 1977;White et al. 1986;Chapman et al. 2008). The posterior migration of QL descendants requires the activity of the MAB-5/Hox transcription factor, expression of which is induced in QL descendants by an EGL-20/Wnt signal emanating from the posterior (Chalfie et al.

Transmembrane protein MIG-13 links the Wnt signaling and Hox genes to the cell polarity in neuronal migration

“…Several transmembrane proteins, DPY-19, MIG-21, UNC-40/DCC (Deleted in Colorectal Cancer), and NF-κB-inducing kinase (NIK) MIG-15, regulate the initial Q-neuroblast polarization, and mutations of these genes reduced Q-neuroblast polarization (8)(9)(10)(11). The C. elegans Wnt/β-catenin pathway activates the expression of the Antennapedia-like Homeobox(Hox) gene mab-5, which is necessary and sufficient to ensure the posterior migration of QL.a (the anterior descendant of QL) and QL.ap (the posterior descendant of QL.a) (12)(13)(14)(15)(16)(17).…”

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).…”

“…To score Q-cell protrusions, animals with expression of GFP in the Q neuroblasts from the egl-17 promoter (ayIs9) were synchronized to 1-2.5 hr posthatching (Chapman et al 2008;Sundararajan and Lundquist 2012). Briefly, gravid adults were allowed to lay eggs overnight.…”

“…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).…”

Nonautonomous Roles of MAB-5/Hox and the Secreted Basement Membrane Molecule SPON-1/F-Spondin in Caenorhabditis elegans Neuronal Migration

“…We used transgenic RNAi of spon-1 driven from the myo-3, egl-17, and scm promoters to knock down spon-1 (Esposito et al 2007;Sundararajan and Lundquist 2012). Alone, Pmyo-3:: spon-1(RNAi) weakly affected AQR (1% defective) migration (Table 1).…”