title: Dendritic mRNA targeting of Jacob and N-methyl-d-aspartate-induced nuclear translocation after calpain-mediated proteolysis.
abstract: Jacob is a recently identified plasticity-related protein that couples N-methyl-d-aspartate receptor activity to nuclear gene expression. An expression analysis by Northern blot and in situ hybridization shows that Jacob is almost exclusively present in brain, in particular in the cortex and the limbic system. Alternative splicing gives rise to multiple mRNA variants, all of which exhibit a prominent dendritic localization in the hippocampus. Functional analysis in primary hippocampal neurons revealed that a predominant cis-acting dendritic targeting element in the 3'-untranslated region of Jacob mRNAs is responsible for dendritic mRNA localization. In the mouse brain, Jacob transcripts are associated with both the fragile X mental retardation protein, a well described trans-acting factor regulating dendritic mRNA targeting and translation, and the kinesin family member 5C motor complex, which is known to mediate dendritic mRNA transport. Jacob is susceptible to rapid protein degradation in a Ca(2+)- and Calpain-dependent manner, and Calpain-mediated clipping of the myristoylated N terminus of Jacob is required for its nuclear translocation after N-methyl-d-aspartate receptor activation. Our data suggest that local synthesis in dendrites may be necessary to replenish dendritic Jacob pools after truncation of the N-terminal membrane anchor and concomitant translocation of Jacob to the nucleus.
authors.affiliation: Institute of Human Genetics, University Medical Center Hamburg Eppendorf, 20246 Hamburg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kindler
authors.forename: Daniela C
authors.initials: DC
authors.lastname: Dieterich
authors.forename: Janin
authors.initials: J
authors.lastname: Schütt
authors.forename: Jale
authors.initials: J
authors.lastname: Sahin
authors.forename: Anna
authors.initials: A
authors.lastname: Karpova
authors.forename: Marina
authors.initials: M
authors.lastname: Mikhaylova
authors.forename: Claudia
authors.initials: C
authors.lastname: Schob
authors.forename: Eckart D
authors.initials: ED
authors.lastname: Gundelfinger
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Kreienkamp
authors.forename: Michael R
authors.initials: MR
authors.lastname: Kreutz
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D002154:Calpain / Q000737:chemistry / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D003712:Dendrites / Q000378:metabolism*; D005822:Genetic Vectors; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000378:metabolism / Q000502:physiology*; D016376:Oligonucleotides, Antisense / Q000737:chemistry; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism* / Q000502:physiology; D014018:Tissue Distribution; D014158:Transcription, Genetic
chemical_list: C544462:Jacob protein, mouse; D009419:Nerve Tissue Proteins; C504443:Nsmf protein, rat; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D002154:Calpain