Disease relevance of SLIT3

• In primary tumours, SLIT3 was methylated in 16% of primary breast tumours, 35% of gliomas and 38% of colorectal tumours [1].
• SLIT2 and SLIT3 mRNAs were co-expressed in embryonic stem (ES) cells with embryoid body formation, and diffuse type gastric cancer with signet ring cell features [2].
• In contrast, the expression of slit2 mRNA increased in most of the malignant mammary tumors, and an increase in slit3 mRNA expression was observed in 2 of the malignant mixed tumors [3].
• Inhibition of medulloblastoma cell invasion by Slit [4].
• SLIT1 mRNA was expressed in fetal brain, infant brain, anaplastic oligodendroglioma, and Jurkat T cells [2].

Psychiatry related information on SLIT3

• A recent report suggested SLITRK1 (Slit and Trk-like 1) as a candidate gene for Tourette Syndrome (TS) [5].
• Compared with the Dilated group, the Slit-like group showed significantly rapid deterioration into lethargy after shunt obstruction [6].

High impact information on SLIT3

• Signal transduction in neuronal migration: roles of GTPase activating proteins and the small GTPase Cdc42 in the Slit-Robo pathway [7].
• The Slit protein guides neuronal and leukocyte migration through the transmembrane receptor Roundabout (Robo) [7].
• Outgrowing axons are routed towards the hippocampal formation by specific expression of long-range cues, which include secreted class 3 semaphorins, netrin 1 and Slit proteins [8].
• Here, using genetics, biochemistry, and cell biology, we demonstrate that Sos is recruited to the plasma membrane, where it forms a ternary complex with the Roundabout receptor and the SH3-SH2 adaptor protein Dreadlocks (Dock) to regulate Rac-dependent cytoskeletal rearrangement in response to the Slit ligand [9].
• (2002 [this issue of Neuron]) demonstrate that in addition to their roles in axon guidance and cell migration cue, Slit proteins can also regulate dendritic growth [10].

Chemical compound and disease context of SLIT3

• AIMS: To assess the effects of (1) mydriasis and (2) single versus three field photography on screening for diabetic eye disease using digital photography METHOD: Slit lamp examination findings were compared to digital fundal photographs for the detection of any retinopathy and for referable retinopathy in 398 patients (794 eyes) [11].
• Re: Slit grafting: the use of serrated island grafts in male and female-pattern alopecia. J Dermatol Surg Oncol 1991;17:243-53 [12].

Biological context of SLIT3

• Methylation was however rarely observed in cell lines for SLIT3 (18%) and DLC1 (18%) [13].
• Comparative genomics on SLIT1, SLIT2, and SLIT3 orthologs [2].
• Here, comparative integromics analyses on SLIT1, SLIT2, and SLIT3 orthologs were performed by using bioinformatics [2].
• In Drosophila, the Slit gene product, a secreted glycoprotein, acts as a midline repellent to guide axonal development during embryogenesis [1].
• Three human Slit gene orthologues have been characterised and recently we reported frequent promoter region hypermethylation and transcriptional silencing of SLIT2 in lung, breast, colorectal and glioma cell lines and primary tumours [1].

Anatomical context of SLIT3

• SLIT3 was found to be methylated in 12 out of 29 (41%) of breast, one out of 15 (6.7%) lung, two out of six (33%) colorectal and in two out of (29%) glioma tumour cell lines [1].
• Dual trafficking of Slit3 to mitochondria and cell surface demonstrates novel localization for Slit protein [14].
• In the present study, we observe that both Slit1 and Slit3 repel and inhibit neurite growth of fetal DA neurons [15].
• In humans, slit2 protein attracts endothelial cells and promotes tube formation in the tumor angiogenic mechanism [3].
• These results suggest that the expression of slit2 plays an important role in tumor angiogenesis in canine mammary gland tumors and that slit2 can be a putative marker for malignancy diagnosis of these tumors [3].

Associations of SLIT3 with chemical compounds

• In tumour cell lines, silenced SLIT3 associated with hypermethylation and was re-expressed after treatment with 5-aza-2'-deoxycytidine [1].
• Mutation of conserved basic residues in the C-terminal cap region of Slit D2 reduces heparin binding and abolishes biological activity [16].
• At this time interval an effect on methacholine challenge was also seen in SLIT 3 [17].
• Glypican binding to Slit was also decreased 80--90% by heparin (2 microg/ml), enzymatic removal of the heparan sulfate chains, and by chlorate inhibition of glypican sulfation [18].
• Multiple dosing of prostaglandin F2 alpha or epinephrine on cynomolgus monkey eyes. II. Slit-lamp biomicroscopy, aqueous humor analysis, and fluorescein angiography [19].

Other interactions of SLIT3

• Similar to SLIT2 expression profile, SLIT3 is expressed strongly in many tissues, while SLIT1 expression is neuronal specific [1].
• We analysed the 5' CpG island of SLIT3 and SLIT1 genes in tumour cell lines and primary tumours for hypermethylation [1].

Analytical, diagnostic and therapeutic context of SLIT3

• However, unlike fetal DA neurites, no directed neurite outgrowth was observed in the cocultures of ES-derived DA neurons with Netrin-1-, Slit1-, and Slit3-producing cells [15].
• Analytical gel filtration chromatography demonstrates that Slit D2 associates with a soluble Robo fragment and a heparin-derived oligosaccharide to form a ternary complex [16].
• Co-transfection of 293 cells with Slit and glypican-1 cDNAs followed by immunoprecipitation demonstrated that these interactions also occur in vivo, and immunocytochemical studies showed colocalization in the embryonic and adult central nervous system [18].
• In conclusion, we report an altered expression and redistribution of Robo2 and Slit1 in the DRG and sciatic nerve trunk after peripheral axotomy [20].
• By contrast, injury to the central axons of the DRG by dorsal rhizotomy did not up-regulate Slit1 and Robo2 expression [20].

References