{
  "abstract": "Hox genes have been broadly implicated in nervous system development, but the molecular and genetic mechanisms that act downstream of Hox factors remain to be identified. The MAB-5 antennapedia-like Hox transcription factor is both necessary and sufficient to cause posterior migration of the Q neuroblast descendants in Caenorhabditis elegans. In response to MAB-5, the left-side QL descendants QL.a and QL.ap undergo a three-stage migration process, with each stage characterized by a posterior lamellipodial protrusion followed by cell body migration. The QL.ap cell differentiates into the PQR neuron posterior to the anus. Previous studies showed that the MAB-5-regulated gene efn-4/Ephrin was required for the third and final stage of QL.ap migration, with efn-4 mutation resulting in placement of PQR immediately anterior to the anus. This subtle and previously-undescribed phenotype opens the possibility that other known neuronal development genes could be involved. In this work, we screened known signaling mutants for third-stage PQR migration defects. We found that mutations in SAX-3/Robo signaling, UNC-6/Netrin signaling, and heparan sulfate proteoglycans (HSPGs) all displayed third-stage PQR migration defects. The effects in single mutants were weak compared to efn-4, and double mutant analysis revealed lack of genetic synergy, consistent with all of these molecules converging on a common pathway. This genetic analysis is consistent with physical interaction studies in vitro from another group that suggest that these molecules form connected communities of interacting extracellular domains, raising the possibility that they are all components of a large extracellular signaling complex required for posterior QL.ap migration. In this model, we envision that MAB-5/Hox drives EFN-4/Ephrin expression in QL.ap, which then seeds the formation of an extracellular signaling complex containing SAX-3/Robo signaling, UNC-6/Netrin signaling, and HSPGs that drives posterior lamellipodial formation and posterior migration. Author summary: The migration of neuroblasts and neurons is key to proper nervous system development. For example, migration of neurons in the developing brain result in the layers of the cerebellar and cerebral cortices, and migration of neural crest cells form the dorsal root ganglia of the peripheral nervous system. In the model organism nematode worm Caenorhabditis elegans, the bilateral Q neuroblasts represent a simple and genetically-tractable model for neuronal migration. QL on the left side of the animal and QR on the right side undergo an identical pattern of division and differentiation into three neurons. The difference is that QL and descendants migrate posteriorly and QR and descendants migrate anteriorly. The Antennapedia-like Hox transcription factor MAB-5 is both necessary and sufficient to drive posterior migration and normally does so in QL. The QL descendant neuron QL.ap undergoes three distinct posterior migrations controlled by MAB-5, with the third and final migration of QL.ap posterior to the anus where differentiation into the PQR neuron occurs. Previous work showed that MAB-5-dependent expression of EFN-4/Ephrin in QL.ap is required for the final stage of QL.ap migration. In this work, we show that multiple other signaling pathways converge with EFN-4/Ephrin to control posterior QL.ap migration, including SAX-3/Robo, UNC-6/Netrin, and Heparan Sulfate Proteoglycans (HSPGs). Our results suggest the novel idea that EFN-4 expression, in response to MAB-5, seeds the formation of a large extracellular signaling complex including components of SAX-3/Robo, UNC-6/Netrin, and HSPGs that is required for posterior QL.ap migration, possible via a novel EFN-4 reverse signaling event in QL.ap.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Molecular Biosciences, The University of Kansas, Lawrence, Kansas, United States of America",
    "Computational Chemical Biology and Molecular Modeling Core Laboratory, The University of Kansas, Lawrence, Kansas, United States of America"
  ],
  "article_type": "Research Article",
  "arxiv": null,
  "author_total": 4,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Vedant D. Jain"
    },
    {
      "affs": [
        1
      ],
      "name": "Andrew M. Johannesen"
    },
    {
      "name": "Felipe L. Teixeira"
    },
    {
      "name": "Erik A. Lundquist"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/90vyt7q9wyyb5.bib",
  "cited_by": 0,
  "doi": "10.1371/journal.pgen.1012303",
  "fulltext_url": "https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012303",
  "id": "90vyt7q9wyyb5",
  "issns": [
    "1553-7404"
  ],
  "landing_url": "https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012303",
  "language": null,
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2804|Axon Guidance and Neuronal Signaling"
    ],
    [
      "plos",
      "/Biology and life sciences/Anatomy/Digestive system/Gastrointestinal tract/Anus"
    ],
    [
      "plos",
      "/Biology and life sciences/Cell biology/Cell motility/Cell migration/Neuron migration"
    ],
    [
      "plos",
      "/Biology and life sciences/Cell biology/Cellular structures and organelles/Cell signaling structures/Signaling complexes"
    ],
    [
      "plos",
      "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Neuroblasts"
    ],
    [
      "plos",
      "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Neurons"
    ],
    [
      "plos",
      "/Biology and life sciences/Developmental biology/Cell differentiation/Neuronal differentiation"
    ],
    [
      "plos",
      "/Biology and life sciences/Developmental biology/Cell migration/Neuron migration"
    ],
    [
      "plos",
      "/Biology and life sciences/Genetics"
    ],
    [
      "plos",
      "/Biology and life sciences/Neuroscience/Cellular neuroscience/Neurons"
    ],
    [
      "plos",
      "/Biology and life sciences/Psychology/Behavior/Animal behavior/Animal migration"
    ],
    [
      "plos",
      "/Biology and life sciences/Zoology/Animal behavior/Animal migration"
    ],
    [
      "plos",
      "/Medicine and health sciences/Anatomy/Digestive system/Gastrointestinal tract/Anus"
    ],
    [
      "plos",
      "/Social sciences/Psychology/Behavior/Animal behavior/Animal migration"
    ]
  ],
  "openalex": "W7144208162",
  "pdf_url": "https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1012303&type=printable",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-08",
  "publisher": "Public Library of Science",
  "ris": "https://research.draconitic.com/paper/90vyt7q9wyyb5.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:56Z",
      "native_id": "10.1371/journal.pgen.1012303",
      "source": "plos",
      "url": "https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012303"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "plos:cell biology",
      "subfield": "cell-biology"
    },
    {
      "field": "biology",
      "origin": "plos:animal behavior",
      "subfield": "zoology-behaviour"
    },
    {
      "field": "medicine",
      "origin": "plos:anatomy",
      "subfield": "physiology"
    }
  ],
  "title": "EFN-4/Ephrin converges with SAX-3/Robo, UNC-6/Netrin, and Heparan Sulfate Proteoglycan signaling to control MAB-5/Hox-dependent posterior Q neuroblast migration in Caenorhabditis elegans",
  "title_text": "EFN-4/Ephrin converges with SAX-3/Robo, UNC-6/Netrin, and Heparan Sulfate Proteoglycan signaling to control MAB-5/Hox-dependent posterior Q neuroblast migration in Caenorhabditis elegans",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:17:56Z",
  "url": "https://research.draconitic.com/paper/90vyt7q9wyyb5",
  "venue": "PLOS Genetics",
  "versions": []
}