The MAM domain-containing GPI anchor proteins MDGA1 and MDGA2 are Ig superfamily adhesion molecules composed of six IG domains, a fibronectin III domain, a MAM domain, and a GPI anchor. MDGAs contribute to the radial migration and positioning of a subset of cortical neurons during early neural development. However, MDGAs continue to be expressed in postnatal brain, and their functions during postnatal neural development remain unknown. Here, we demonstrate that MDGAs specifically and with a nanomolar affinity bind to neuroligin-2, a cell-adhesion molecule of inhibitory synapses, but do not bind detectably to neuroligin-1 or neuroligin-3. We observed no cell adhesion between cells expressing neuroligin-2 and MDGA1, suggesting a cis interaction. Importantly, RNAi-mediated knockdown of MDGAs increased the abundance of inhibitory but not excitatory synapses in a neuroligin-2-dependent manner. Conversely, overexpression of MDGA1 decreased the numbers of functional inhibitory synapses. Likewise, coexpression of both MDGA1 and neuroligin-2 reduced the synaptogenic capacity of neuroligin-2 in an artificial synapse-formation assay by abolishing the ability of neuroligin-2 to form an adhesion complex with neurexins. Taken together, our data suggest that MDGAs inhibit the activity of neuroligin-2 in controlling the function of inhibitory synapses and that MDGAs do so by binding to neuroligin-2.inhibitory synapse formation | synaptic cell adhesion | autism | schizophrenia R ecent studies of synapse formation have uncovered a multitude of synaptic adhesion molecules, and human genetic studies have implicated many of these molecules in neuropsychiatric and neurodevelopmental disorders (1-4). However, little is known about the specific pathophysiological mechanisms by which dysfunctions of synaptic adhesion molecules contribute to these complex disorders.Neurexins and neuroligins (NLs) are arguably the most extensively studied synaptic adhesion molecules (1). They are dispensable for initial synapse establishment but act in an isoformdependent manner to specify the maturation of either excitatory or inhibitory synapses (5). There are four NL members in rodents (NL1-NL4) that show distinct synaptic localizations and functions (5). NL2, in particular, has received considerable attention because of its unique localization and function at inhibitory synapses (6). For instance, NL2 controls perisomatic inhibitory synapse maturation together with gephyrin and collybistin, which regulate GABA receptor clustering on neurons (7,8). Moreover, NL2 exhibits differential functions at different types of inhibitory synapses on the same postsynaptic neuron (9). All four NLs likely mediate synapse-promoting activities through direct interactions with presynaptic neurexins, but NLs also perform additional functions in synapse validation that are independent of their binding to neurexins (10).MAM domain-containing GPI anchor proteins (MDGAs), also termed "GPIMs" or "MAMDCs," initially were identified in tumor cells (11). The two homologous MDGA ...

Bone homeostasis depends on the coordination of osteoclastic bone resorption and osteoblastic bone formation. Receptor activator of NF-B ligand (RANKL) induces osteoclast differentiation through activating a transcriptional program mediated by the key transcription factor nuclear factor of activated T cells (NFAT) c1. Immunoreceptors, including osteoclast-associated receptor (OSCAR) and triggering receptor expressed by myeloid cells (TREM)-2, constitute the co-stimulatory signals required for RANKL-mediated activation of calcium signaling, which leads to the activation of NFATc1. However, it remains unknown whether the expression of immunoreceptors are under the control of NFATc1. Here we demonstrate that the expression of OSCAR, but not that of TREM-2, is up-regulated during osteoclastogenesis and markedly suppressed by the calcineurin inhibitor FK506, suggesting that OSCAR is transcriptionally regulated by NFATc1. NFATc1 expression results in the activation of the OSCAR promoter, which was found to be further enhanced by co-expression of PU.1 and microphthalmia-associated transcription factor (MITF). We further provide evidence that NFATc1 specifically regulates OSCAR by chromatin immunoprecipitation assay and quantification of OSCAR and TREM-2 mRNA in NFATc1 Bone is continuously remodeled by a series of cellular actions of boneresorbing osteoclasts and bone-forming osteoblasts. Osteoclasts are the primary cells that resorb bone, and our knowledge concerning the mechanisms of osteoclast differentiation has been increasing rapidly (1-4). The finding that bone marrow monocyte/macrophage lineage cells (BMMs) 2 can differentiate into osteoclasts in vitro when co-cultured with osteoblasts (5) suggested that osteoblast-derived factors induce osteoclast differentiation. Receptor activator of NF-B ligand (RANKL) and macrophage-colony stimulating factor (M-CSF) are provided by osteoblasts and essential for osteoclastogenesis (1-4). In addition, we discovered recently that the immunoreceptor-mediated calcium signals are also critical for osteoclastogenesis (6).In the osteoclast differentiation program, transcription factor nuclear factor of activated T cells (NFAT) c1 is induced significantly by RANKL (7). NFATc1 is involved in the transcriptional regulation of osteoclastspecific genes, such as ACP5 (encoding tartrate-resistant acid phosphatase (TRAP)) (7), calcitonin receptor (7,8), and cathepsin K (9). Moreover, NFATc1-deficient embryonic stem cells failed to differentiate into osteoclasts in vitro, and ectopic expression of NFATc1 caused induction of osteoclast differentiation even in the absence of RANKL (7). Thus, NFATc1 can be referred to as the master transcription factor for osteoclastogenesis.The activity of NFATc1 is controlled by the phosphatase calcineurin, which plays a critical role in the coupling of calcium signals with cellular responses (10 -13). Once activated by an increase of the intracellular calcium concentration, calcineurin induces the translocation of NFATc1 into the nucleus, where it activat...

Objective: To test the hypothesis that there is no difference in the vertical alveolar bone levels and alveolar bone thickness around the maxillary and mandibular central incisors in surgically treated skeletal Class III malocclusion patients. Materials and Methods:The study sample comprised 20 Korean patients with skeletal Class III malocclusion with anterior crossbite and openbite (9 male, 11 female, mean ages 24.1). Threedimensional cone beam computed tomography images were taken at least 1 month before the orthognathic surgery, and sagittal slices chosen at the labio-lingually widest point of the maxillary and mandibular right central incisor were evaluated. Measurement of the amount of vertical alveolar bone levels and alveolar bone thickness of the labial and lingual plate at the root apex was made using the SimPlant Pro 12.0 program. Results:The mandibular incisors showed reduced vertical alveolar bone levels than the maxillary incisors, especially on the lingual side. The alveolar bone thickness was significantly greater on the lingual side in the maxillary incisors, whereas the mandibular incisors exhibited an opposite result (P Ͻ .05). The percentage of vertical bone loss to root length showed a statistically significant difference between the upper labial and lower labial alveolar bone and also between the upper lingual and lower lingual alveolar bone, showing more bone loss in the lower incisors (P Ͻ .001). Conclusions:The hypothesis is rejected. For the skeletal Class III patients undergoing orthognathic surgery, special care should be taken to prevent or not aggravate preexisting alveolar bone loss in the anterior teeth, especially in the mandible. (Angle Orthod. 2009;79:676-682.)