The requirement for Phr1 in CNS axon tract formation reveals the corticostriatal boundary as a choice point for cortical axons.
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.
Bloom
A Joseph
AJ
Department of Molecular Biology and Pharmacology, Washington University, Saint Louis, Missouri 63110, USA.
Miller
Bradley R
BR
Sanes
Joshua R
JR
DiAntonio
Aaron
A
D061085:Agenesis of Corpus Callosum; D000818:Animals; D001369:Axons / Q000648:ultrastructure; D001483:Base Sequence; D002490:Central Nervous System / Q000002:abnormalities / Q000196:embryology*; D002540:Cerebral Cortex / Q000196:embryology; D003337:Corpus Callosum / Q000196:embryology; D003342:Corpus Striatum / Q000196:embryology; D017931:DNA Primers / Q000235:genetics; D015536:Down-Regulation; D019143:Evolution, Molecular; D005260:Female; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000502:physiology; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009469:Neuromuscular Junction / Q000196:embryology; D010641:Phenotype; D011247:Pregnancy; D012165:Retinal Ganglion Cells / Q000166:cytology; D013788:Thalamus / Q000196:embryology
D017931:DNA Primers; D008565:Membrane Proteins; C485943:Plekhb1 protein, mouse; D020930:MAP Kinase Kinase Kinases