Abstract
RanBP9 is known to act as a scaffolding protein bringing together a variety of cell surface receptors and intracellular targets thereby regulating functions as diverse as neurite and axonal outgrowth, cell morphology, cell proliferation, myelination, gonad development, myofibrillogenesis and migration of neuronal precursors. Though RanBP9 is ubiquitously expressed in all tissues, brain is one of the organs with the highest expression levels of RanBP9. In the neurons, RanBP9 is localized mostly in the cytoplasm but also in the neurites and dendritic processes. We recently demonstrated that RanBP9 plays pathogenic role in Alzheimer’s disease. To understand the role of RanBP9 in the brain, here we generated RanBP9 null mice by gene-trap based strategy. Most of Ran−/− mice die neonatally due to defects in the brain growth and development. The major defects include smaller cortical plate (CP), robustly enlarged lateral ventricles (LV) and reduced volume of hippocampus (HI). The lethal phenotype is due to a suckling defect as evidenced by lack of milk in the stomachs even several hours after parturition. The complex somatosensory system which is required for a behavior such as suckling appears to be compromised in Ran−/− mice due to under developed CP. Most importantly, RanBP9 phenotype is similar to ERK1/2 double knockout and the neural cell adhesion receptor, L1CAM knockout mice. Both ERK1 and L1CAM interact with RanBP9. Thus, RanBP9 appears to control brain growth and development through signaling mechanisms involving ERK1 and L1CAM receptor.
Highlights
Ran-binding protein 9 (RanBP9) called RanBPM is a multi-modular scaffolding protein implicated in a variety of functions through integration of cell surface receptors with intracellular signaling targets [1,2]
Characterization of RanBP9 Null Mice The germ line transmission of the mutated RanBP9 allele was initially confirmed by PCR amplification of b-gal gene from the total genomic DNA extracted from the tails using the forward primer, 59-TTA TCG ATG AGC GTG GTG GTT ATG C-39 and the reverse primer, 59-GCG CGT ACA TCG GGC AAA TAA TAT C-39
Because successful inactivation of trapped gene is expected to produce Ran-bgeo mutant fusion protein, we re-probed the blots and confirmed the expression of high molecular weight Ran-bgeo mutant fusion protein detected by an antibody that recognizes bgalactosidase (Fig. 1C, middle panel) suggesting that the complete absence of RanBP9 protein is the result of the mutant fusion protein produced by gene-trapping
Summary
Ran-binding protein 9 (RanBP9) called RanBPM is a multi-modular scaffolding protein implicated in a variety of functions through integration of cell surface receptors with intracellular signaling targets [1,2]. RanBP9 is well conserved in organisms at all levels of evolution starting from xenopus to human. Sequence homology search using prosite identifies several conserved domains implicated in a variety of functions. The LisH (Lissencephaly type-1 like homology) domain has been implicated in protein dimerization or oligomerization [5,6]. The CTLH (C-terminal to LisH) domain function is unknown. The CRA (CT11-RanBP9) domain at the cterminal end of RanBP9 is a protein-protein interaction domain shown to bind fragile X mental retardation protein (FMRP) in the microtubule organizing center [7]
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