New roles for Hox and Wnt in Cell Migration
Josephson, Matthew P.
University of Kansas
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Neuron migration is a critical process during central nervous system development. In the dissertation below I report new roles for established genes such as Wnt and Hox, and describe roles for several new genes in neuron migration. To study migrating neurons I use the model organism nematode worm Caenorhabditis elegans. With only 302 neurons, C. elegans is an excellent model to examine migration of individual neurons. The QR and QL neuroblasts are two bilaterally symmetric neural progenitor cells born in the posterior region of the worm. Although born in the same area, these cells undergo opposite directions of migration. QR migrates anteriorly, and QL migrates posteriorly. In QL, detection of extracellular EGL-20/Wnt results in trasncription of mab-5/Antennapedia/Hox through canonical Wnt signalling. MAB-5 is a posterior migration determinant of the QL lineage, and expression of mab-5 is necessary and sufficient for posterior migration. lin-39/Sex combs reduced/Hox is activated through unknown mechanisms in QR and promotes anterior migration of that lineage. lin-39 and mab-5 are well studied genes than have been implicated in cell-autonomous control of Q migrations. After an introduction to Q cell migration in chapter I, chapter II describes new roles for Hox gene in Q descendant migration that may change the way we think about how Hox genes work. I show that lin-39, mab-5 and a third Hox gene egl-5/Abdominal-B/Hox act in parallel to promote migration of the Q cells, and in their absence almost no migration occurs. This in contrast to the typical opposing roles of Hox genes whereby lin-39 promotes anterior migration of QR lineage, and mab-5 promotes posterior migration of the QL lineage. I also find that mab-5, and egl-5 are able to promote Q migration through their expression in posterior body wall muscles, a non-autonomous role in migration. Again this shifts how Hox genes should be considered, as they are often thought to act solely as autonomous drivers of cell fate and to have opposing roles in differentiation. As a Hox factor mab-5 regulates many genes, but few mab-5 targets have been identified. Results in this dissertation show that mab-5 may regulate the secreted F-spondin homolog spon-1 to control migration. I demonstrate that the spon-1 promoter can be driven by MAB-5 in the body wall muscles, and that spon-1 is important in Q cell direction and extent of migration. Chapter III presents new roles for egl-20/Wnt and mab-5/Hox in inhibiting anterior migration. Detailed analysis of the timing of Q descendant migration reveals that egl-20/Wnt can act in two steps to inhibit anterior migration and promote posterior migration of the QL linage. (i) Through an acute non-canonical Wnt mechanism EGL-20 inhibits anterior migration, and (ii) later, through canonical Wnt pathway activates transcription of mab-5 which can further inhibit anterior migration and promote further migration of the QL lineage. The first characterization of the C. elegans Neurofibromatosis Type II(NF2)/Merlin homolog nfm-1 is detailed in chapter IV. Previously in the Lundquist lab an unbiased forward genetic screen identified an allele of nfm-1 is required for Q descendant migration. I show that nfm-1 promotes migration of QR and QL lineages through non-autonomous mechanisms, and can act genetically, possibly in the same pathway with the guidance cue slt-1/Slit, to promote complete migration of the QR and QL lineages. The results contained below use new techniques to study established and novel genes in nervous system development, highlighting the intricacies of developmental genetics. Many genes play multiple roles in development, demonstrated here by new roles for Hox and Wnt in Q cell migration.
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