24 research outputs found
SALM5 trans-synaptically interacts with LAR-RPTPs in a splicing-dependent manner to regulate synapse development
Synaptogenic adhesion molecules play critical roles in synapse formation. SALM5/Lrfn5, a SALM/Lrfn family adhesion molecule implicated in autism spectrum disorders (ASDs) and schizophrenia, induces presynaptic differentiation in contacting axons, but its presynaptic ligand remains unknown. We found that SALM5 interacts with the Ig domains of LAR family receptor protein tyrosine phosphatases (LAR-RPTPs; LAR, PTPĪ“, and PTPĻ). These interactions are strongly inhibited by the splice insert B in the Ig domain region of LAR-RPTPs, and mediate SALM5-dependent presynaptic differentiation in contacting axons. In addition, SALM5 regulates AMPA receptor-mediated synaptic transmission through mechanisms involving the interaction of postsynaptic SALM5 with presynaptic LAR-RPTPs. These results suggest that postsynaptic SALM5 promotes synapse development by trans-synaptically interacting with presynaptic LAR-RPTPs and is important for the regulation of excitatory synaptic strength
MSX1 Polymorphism Associated with Risk of Oral Cleft in Korea: Evidence from Case-Parent Trio and Case-Control Studies
Orofacial clefts, including cleft lip with or without palate (CL/P) and cleft palate (CP), are one of the most common congenital malformations in Asian populations, where the rate of incidence is higher than in European or other racial groups. A number of candidate genes have been identified for orofacial clefts, although no single candidate has been consistently identified in all studies. We performed case-parent trio and case-control studies on 6 single nucleotide polymorphisms (SNPs) in the MSX1 gene using a sample of 52 CL/P and CP probands from Korea. In the case-control study, the allele frequencies of 6 MSX1 SNPs were compared between 52 oral cleft cases and 96 unmatched controls. For the case-parent trio study, single-marker and haplotype-based tests of transmission disequilibrium using allelic and genotypic tests revealed significant evidence of linkage in the presence of disequilibrium for 1170 G/A of exon 2. With the GG genotype as a reference group among GG, GA, and AA genotypes at 1170G/A, the disease risk decreased with the presence of the A allele (AA genotype: OR = 0.26, 95% CI = 0.10-0.99). These results are consistent with evidence from other studies in the US and Chile and confirm the importance of the MSX1 genotype in determining the risk of CL/P and CP in Koreans
Formulation optimization and in vivo proof-of-concept study of thermosensitive liposomes balanced by phospholipid, elastin-like polypeptide, and cholesterol.
One application of nanotechnology in medicine that is presently being developed involves a drug delivery system (DDS) employing nanoparticles to deliver drugs to diseased sites in the body avoiding damage of healthy tissue. Recently, the mild hyperthermia-triggered drug delivery combined with anticancer agent-loaded thermosensitive liposomes was widely investigated. In this study, thermosensitive liposomes (TSLs), composed of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol)-2000] (DSPE-PEG), cholesterol, and a fatty acid conjugated elastin-like polypeptide (ELP), were developed and optimized for triggered drug release, controlled by external heat stimuli. We introduced modified ELP, tunable for various biomedical purposes, to our thermosensitive liposome (e-TSL) to convey a high thermoresponsive property. We modulated thermosensitivity and stability by varying the ratios of e-TSL components, such as phospholipid, ELP, and cholesterol. Experimental data obtained in this study corresponded to results from a simulation study that demonstrated, through the calculation of the lateral diffusion coefficient, increased permeation of the lipid bilayer with higher ELP concentrations, and decreased permeation in the presence of cholesterol. Finally, we identified effective drug accumulation in tumor tissues and antitumor efficacy with our optimized e-TSL, while adjusting lag-times for systemic accumulation
SALM5 trans-synaptically interacts with LAR-RPTPs in a splicing-dependent manner to regulate synapse development
Synaptogenic adhesion molecules play critical roles in synapse formation. SALM5/Lrfn5, a SALM/Lrfn family adhesion molecule implicated in autism spectrum disorders (ASDs) and schizophrenia, induces presynaptic differentiation in contacting axons, but its presynaptic ligand remains unknown. We found that SALM5 interacts with the Ig domains of LAR family receptor protein tyrosine phosphatases (LAR-RPTPs; LAR, PTPĪ“, and PTPĻ). These interactions are strongly inhibited by the splice insert B in the Ig domain region of LAR-RPTPs, and mediate SALM5-dependent presynaptic differentiation in contacting axons. In addition, SALM5 regulates AMPA receptor-mediated synaptic transmission through mechanisms involving the interaction of postsynaptic SALM5 with presynaptic LAR-RPTPs. These results suggest that postsynaptic SALM5 promotes synapse development by trans-synaptically interacting with presynaptic LAR-RPTPs and is important for the regulation of excitatory synaptic strength.113131sciescopu
Slitrks control excitatory and inhibitory synapse formation with LAR receptor protein tyrosine phosphatases
The balance between excitatory and inhibitory synaptic inputs,
which is governed by multiple synapse organizers, controls neural
circuit functions and behaviors. Slit- and Trk-like proteins (Slitrks) are
a family of synapse organizers, whose emerging synaptic roles are
incompletely understood. Here, we report that Slitrks are enriched
in postsynaptic densities in rat brains. Overexpression of Slitrks
promoted synapse formation, whereas RNAi-mediated knockdown
of Slitrks decreased synapse density. Intriguingly, Slitrks
were required for both excitatory and inhibitory synapse formation
in an isoform-dependent manner. Moreover, Slitrks required distinct
members of the leukocyte antigen-related receptor protein
tyrosine phosphatase (LAR-RPTP) family to trigger synapse formation.
Protein tyrosine phosphatase Ļ (PTPĻ), in particular, was specifically
required for excitatory synaptic differentiation by Slitrks,
whereas PTPĪ“ was necessary for inhibitory synapse differentiation.
Taken together, these data suggest that combinatorial interactions
of Slitrks with LAR-RPTP family members maintain synapse formation
to coordinate excitatoryāinhibitory balance.11sciescopu
The adhesion protein IgSF9b is coupled to neuroligin 2 via S-SCAM to promote inhibitory synapse development
Synaptic adhesion molecules regulate diverse aspects of synapse formation and maintenance. Many known synaptic adhesion molecules localize at excitatory synapses, whereas relatively little is known about inhibitory synaptic adhesion molecules. Here we report that IgSF9b is a novel, brain-specific, homophilic adhesion molecule that is strongly expressed in GABAergic interneurons. IgSF9b was preferentially localized at inhibitory synapses in cultured rat hippocampal and cortical interneurons and was required for the development of inhibitory synapses onto interneurons. IgSF9b formed a subsynaptic domain distinct from the GABA(A) receptor- and gephyrin-containing domain, as indicated by super-resolution imaging. IgSF9b was linked to neuroligin 2, an inhibitory synaptic adhesion molecule coupled to gephyrin, via the multi-PDZ protein S-SCAM. IgSF9b and neuroligin 2 could reciprocally cluster each other. These results suggest a novel mode of inhibitory synaptic organization in which two subsynaptic domains, one containing IgSF9b for synaptic adhesion and the other containing gephyrin and GABA(A) receptors for synaptic transmission, are interconnected through S-SCAM and neuroligin 2.137381sciescopu
Structural basis for LAR-RPTP/Slitrk complex-mediated synaptic adhesion
Synaptic adhesion molecules orchestrate synaptogenesis. The presynaptic leukocyte
common antigen-related receptor protein tyrosine phosphatases (LAR-RPTPs) regulate
synapse development by interacting with postsynaptic Slit- and Trk-like family proteins
(Slitrks), which harbour two extracellular leucine-rich repeats (LRR1 and LRR2). Here we
identify the minimal regions of the LAR-RPTPs and Slitrks, LAR-RPTPs Ig1ā3 and Slitrks LRR1,
for their interaction and synaptogenic function. Subsequent crystallographic and structureguided
functional analyses reveal that the splicing inserts in LAR-RPTPs are key molecular
determinants for Slitrk binding and synapse formation. Moreover, structural comparison of
the two Slitrk1 LRRs reveal that unique properties on the concave surface of Slitrk1 LRR1
render its specific binding to LAR-RPTPs. Finally, we demonstrate that lateral interactions
between adjacent trans-synaptic LAR-RPTPs/Slitrks complexes observed in crystal lattices
are critical for Slitrk1-induced lateral assembly and synaptogenic activity. Thus, we propose a
model in which Slitrks mediate synaptogenic functions through direct binding to LAR-RPTPs
and the subsequent lateral assembly of LAR-RPTPs/Slitrks complexes.133351sciescopu
DOX release profile of the liposome with the formulations.
<p>DPPC:DSPE-PEG:cholesterolā=ā55ā¶2ā¶15 in the presence/absence of SA-V3 (molar ratioā¶0.41). The amounts of DOX release were measured after 5 min incubation at desired temperature from 25 to 55Ā°C by fluorometry at Ex. 490 nm/Em. 615 nm. Data is shown as mean Ā± S.D. (nā=ā3).</p
Schematic diagram of e-TSL and the chemical structure of ELP-lipid conjugates.
<p>Schematic diagram of e-TSL and the chemical structure of ELP-lipid conjugates.</p