Ror kinases are a family of orphan receptors with tyrosine kinase activity that are related to muscle specific kinase (MuSK), a receptor tyrosine kinase that assembles acetylcholine receptors at the neuromuscular junction. Although the functions of Ror kinases are unknown, similarities between Ror and MuSK kinases have led to speculation that Ror kinases regulate synaptic development. Here we show that the Caenorhabditis elegans gene cam-1 encodes a member of the Ror kinase family that guides migrating cells and orients the polarity of asymmetric cell divisions and axon outgrowth. We find that tyrosine kinase activity is required for some of the functions of CAM-1, but not for its role in cell migration. CAM-1 is expressed in cells that require its function, and acts cell autonomously in migrating neurons. Overexpression and loss of cam-1 function result in reciprocal cell-migration phenotypes, indicating that levels of CAM-1 influence the final positions of migrating cells. Our results raise the possibility that Ror kinases regulate cell motility and asymmetric cell division in organisms as diverse as nematodes and mammals.
Members of the Wnt family of secreted glycoproteins regulate many developmental processes, including cell migration. We and others have previously shown that the Wnts egl-20, cwn-1, and cwn-2 are required for cell migration and axon guidance. However, the roles in cell migration of all of the Caenorhabditis elegans Wnt genes and their candidate receptors have not been explored fully. We have extended our analysis to include all C. elegans Wnts and six candidate Wnt receptors: four Frizzleds, the sole Ryk family receptor LIN-18, and the Ror receptor tyrosine kinase CAM-1. We show that three of the Wnts, CWN-1, CWN-2, and EGL-20, play major roles in directing cell migrations and that all five Wnts direct specific cell migrations either by acting redundantly or by antagonizing each other's function. We report that all four Frizzleds function to direct Q-descendant cell migrations, but only a subset of the putative Wnt receptors function in directing migrations of other cells. Finally, we find striking differences between the phenotypes of the Wnt quintuple and Frizzled quadruple mutants.
A temperature-sensitive lethal mutation in Saccharomyces cerevisiae, prp20-1, causes defects in several different steps in mRNA metabolism, including mRNA 3'-end formation, transcription initiation, and mRNA transport. Previous work has demonstrated that prp20 mutants are defective in actin pre-mRNA splicing. PRP20 is related, both in structure and function, to the RCC1 gene of mammals and the PIM1 gene of Schizosaccharomyces pombe, both of which appear to regulate entry into mitosis and chromosome condensation. In this report we demonstrate that, after a shift of prp20 mutants to the restrictive temperature, transcripts of several genes (CUP1, CYH2, and GALIO) are produced that extend 1-10 kb beyond their normal polyadenylation sites. The failure in 3'-end formation occurs within 1-2 min of the temperature shift. Transcription initiation also is disrupted, in that initiation sites upstream of the normal cap site are used. mRNA transport from nucleus to cytoplasm also is perturbed: In situ hybridization using an oligo(dT) probe demonstrates accumulation of poly(A) in the nucleus, consistent with the accumulation of longer bulk poly(A) (up to -90-100 nucleotides) and with a failure to transport newly synthesized RNA to the cytoplasm. We demonstrate that prp20 and rnal mutants are very similar, if not identical, with respect to each of these biochemical phenotypes. In light of the putative role of PRP20 in mitotic control, our results suggest a common step in that process and multiple steps in mRNA synthesis and maturation. We speculate that the perturbations in mRNA processing are the result of effects on the chromatin-nascent RNP-transcription complex or misregulation of a cell cycle component that modifies multiple mRNA-processing activities.
During Caenorhabditis elegans development, the HSN neurons and the right Q neuroblast and its descendants undergo long-range anteriorly directed migrations. Both of these migrations require EGL-20, a C. elegans Wnt homolog. Through a canonical Wnt signaling pathway, EGL-20/Wnt transcriptionally activates the Hox gene mab-5 in the left Q neuroblast and its descendants, causing the cells to migrate posteriorly. In this report, we show that CAM-1, a Ror receptor tyrosine kinase (RTK) family member, inhibits EGL-20 signaling. Excess EGL-20, like loss of cam-1, caused the HSNs to migrate too far anteriorly. Excess CAM-1, like loss of egl-20, shifted the final positions of the HSNs posteriorly and caused the left Q neuroblast descendants to migrate anteriorly. The reversal in the migration of the left Q neuroblast and its descendants resulted from a failure to express mab-5, an egl-20 mutant phenotype. Our data suggest that CAM-1 negatively regulates EGL-20. In addition to their cell migration defects, cam-1 muneurons migrate posteriorly to positions near the middle of the animal during embryogenesis. Also in emtants fail to properly orient the polarity of specific cells . Six V cells located on each bryos, the hermaphrodite-specific neurons (HSNs) migrate anteriorly from the tail to the middle of the animal, side of the animal divide asymmetrically during the first larval stage to produce an anterior daughter that fuses and the BDU neurons migrate a short distance anteriorly. The left (L) and right (R) Q neuroblasts and their with the syncitial hypodermis and a posterior blast cell (Sulston and Horvitz 1977; Podbilewicz and White descendants (hereafter referred to as QL and QR descendants, respectively) migrate during the first larval 1994). Similarly, the six Pn.aap neuroblasts P3.aap through P8.aap divide asymmetrically in males during stage ( Figure 1B; Sulston and Horvitz 1977). The QL descendants migrate posteriorly, whereas the QR the first larval stage to generate an anterior CA neuron, which accumulates low levels of the neurotransmitter descendants migrate anteriorly.To understand how these long-range cell migrations serotonin, and a posterior CP neuron, which accumulates high levels of serotonin (Sulston et al. 1980; Loer are regulated, we have turned to genetic screens to identify genes that are required for normal cell migraand Kenyon 1993). The fates of the daughter cells of the most anterior V cell (V1) and male Pn.aap neuroblast tion to occur. An example of such a gene is cam-1 (also (P3.aap) often are reversed in cam-1 mutants (Forrescalled kin-8;Koga et al. 1999 Koga et al. ). ter et al. 1999. Finally, the CP neurons of wild-type Mutations in cam-1 cause anterior displacement of the males extend posteriorly directed axons, whereas the final positions of cells that migrate during embryonic most anterior CP neuron of cam-1 mutant males often development. The CAN and ALM neurons, which miextends its axon anteriorly . grate posteriorly during embryogenesis, stop prema-CAM-1 belongs to the Ror c...
We conclude that MIG-10 mediates the guidance of AVM and PVM axons in response to the extracellular UNC-6 and SLT-1 guidance cues. The attractive and repulsive guidance cues orient MIG-10-dependant axon outgrowth to cause a directional response.
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