Disease relevance of Nrt

• Analysis of both loss and gain of gene function conditions during embryonic and postembryonic development revealed specific requirements for neurotactin during axon outgrowth, fasciculation, and guidance [1].
• Now, in this issue of the Biochemical Journal, Takenawa and colleagues have demonstrated that Disabled also acts in a pathway to regulate actin dynamics through the direct activation of N-WASP (neuronal Wiskott-Aldrich syndrome protein) [2].
• ESX is located at chromosome 1q32 in a region known to be amplified in 50% of early breast cancers, is heregulin-inducible and overexpressed in HER2/neu activated breast cancer cells [3].

High impact information on Nrt

• We have isolated and characterized mutations in Drosophila neurotactin, a gene that encodes a cell adhesion protein widely expressed during neural development [1].
• Neurotactin functions in concert with other identified CAMs in growth cone guidance in Drosophila [1].
• Furthermore, AMA is necessary for NRT-expressing cells both to aggregate with themselves and to associate with embryonic primary culture cells [4].
• Pupae deficient for ama do exhibit defasciculation defects of the ocellar nerves similar to those found in nrt mutants [4].
• Here, we identify a mouse homolog of the Drosophila Disabled (Dab) protein, mDab1, and show it is an adaptor molecule functioning in neural development [5].

Biological context of Nrt

• Cell culture experiments demonstrate the Ama(M109) mutant protein binds to Nrt, but is defective in mediating Ama/Nrt cell adhesion [6].
• Heterozygous null alleles of nrt dominantly enhance the Abl mutant phenotype, also affecting axon pathfinding [6].
• By using truncated Nrt molecules and a homotypic cell aggregation assay which involves a soluble ligand activity, it has been possible to show that the adhesive function is localized in the N-terminal region of the extracellular domain comprised between His347 and His482 [7].
• Neurotactin is regionally expressed at the cellular blastoderm stage; later in embryogenesis the expression of the protein becomes restricted to cells of the peripheral and central nervous system [8].
• The extracellular domain at the carboxyterminal end of the neurotactin protein shows a strong structural and sequence homology to serine esterases without retaining the amino acids forming the active center [8].

Anatomical context of Nrt

• These results suggest Ama/Nrt-mediated adhesion may be part of signaling networks involving the Abl tyrosine kinase in the growth cone [6].
• The location at cellular junctions between specific neurons or epithelial cells, the heterophilic binding to a putative ligand and the ability to be phosphorylated are consistent with the suggestion that neurotactin functions as an adhesion molecule [9].
• The fasciculated neurites arising from each cluster of adult-specific neurons express the cell-adhesion protein Neurotactin and they make a complex scaffold of neurite bundles within the thoracic neuropils [10].
• In shibire mutants, the transmembrane protein Neurotactin follows the secretory pathway normally but is not properly inserted in the plasma membrane and accumulates instead in Rab11 subapical endosomes [11].
• Filopodia formation and Disabled degradation downstream of Reelin [2].

Associations of Nrt with chemical compounds

• Interactions between the secreted protein Amalgam, its transmembrane receptor Neurotactin and the Abelson tyrosine kinase affect axon pathfinding [6].
• Neurotactin (Nrt), a Drosophila transmembrane glycoprotein which is expressed in neuronal and epithelial tissues during embryonic and larval stages, exhibits heterophilic adhesive properties [7].
• It has been observed that in female CBA, SHR, SAM and transgenic HER-2/neu mice long-term administration of melatonin was followed by an increase in the mean life span [12].

Other interactions of Nrt

• Amalgam (Ama) is a secreted protein that interacts with the transmembrane protein Neurotactin (Nrt) to promote cell:cell adhesion [6].
• Neurotactin therefore belongs to a growing group of proteins including Drosophila glutactin and thyroglobulins that are known to share this serine esterase protein domain motif without retaining the active center of the enzyme [8].
• These data define three major HRP proteins as neurotactin, fasciclin I, and an R-PTP, DPTP69D [13].
• Neurotactin has a large cytoplasmic domain rich in charged residues and an extracellular domain similar to cholinesterase that lacks the active site serine required for esterase activity [14].

Analytical, diagnostic and therapeutic context of Nrt

• Electron microscopy studies reveal that neurotactin is uniformly expressed along the areas of contacts between cells, without, however, being restricted to a particular type of junction [9].
• Neurotactin is a transmembrane protein, as indicated by epitope mapping and amino acid sequence [14].
• We have studied the spatial distribution of RNA from the neurogenic genes D1, neu, and m4, m5, m7 and E(spl) [four genes of the Enhancer of split complex] in various neurogenic mutant embryos by in situ hybridization [15].

References