The requirement for Phr1 in CNS axon tract formation reveals the corticostriatal boundary as a choice point for cortical axons

A. Joseph Bloom, Bradley R. Miller, Joshua R. Sanes, Aaron DiAntonio

Research output: Contribution to journalArticlepeer-review

101 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)2593-2606
Number of pages14
JournalGenes and Development
Volume21
Issue number20
DOIs
StatePublished - Oct 15 2007

Keywords

  • Axon guidance
  • DLK
  • Internal capsule
  • Neuromuscular junction
  • Synapse formation

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