Journal
GENES & DEVELOPMENT
Volume 21, Issue 20, Pages 2593-2606Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.1592107
Keywords
axon guidance; synapse formation; internal capsule; neuromuscular junction; DLK
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Funding
- NIDA NIH HHS [R01 DA020812-01A2, R01 DA020812] Funding Source: Medline
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Phr1 is the single well-conserved murine ortholog of the invertebrate ubiquitin ligase genes highwire ( in Drosophila) and rpm-1 ( in Caenorhabditis elegans). The function and mechanism of action of highwire and rpm-1 are similar-both cell-autonomously regulate synaptogenesis by down-regulating the ortholog of the mitogen-activated protein kinase kinase kinase dual leucine zipper kinase ( MAPKKK DLK). Here, using a targeted conditional mutant, we demonstrate that Phr1 also plays essential roles in mammalian neural development. As in invertebrates, Phr1 functions cell-autonomously to sculpt motor nerve terminals. In addition, Phr1 plays essential roles in the formation of major CNS axon tracts including those of the internal capsule, in part via cell-nonautonomous mechanisms, and these results reveal a choice point for cortical axons at the corticostriatal boundary. Furthermore, whereas the neurite morphology phenotypes of highwire and rpm-1 are suppressed by loss of DLK in flies and worms, Phr1-dependent CNS defects persist in Phr1, DLK double mutants. Thus, in the mammalian nervous system Phr1 is required for formation of major CNS axon tracts via a mechanism that is both cell-nonautonomous and independent of DLK.
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