In nucleus pulposus cells, the loss of HIF-1a was reported to increase CCN2 expression. Based on these findings, we speculate that in addition to independent CCN2 and HIF-1a induced pathways, there could be interaction between HIF-1a and CCN2 in chordoma cells, such that rCCN2 is decreasing HIF-1a activity under hypoxia but promoting HIF-1a activity under normoxia. Taken together, findings from this study highlight the importance of the tumour microenvironment in the regulation of human chordoma cell phenotype. We demonstrate that components of the microenvironment influence the chordoma cell phenotype and that cells respond to hypoxia and exogenous CCN2 by up-regulating progenitor cell-like properties. Although further studies are required to validate these findings in other chordoma cell lines or primary tumour cells, our findings suggest an intriguing commonality between the pathways associated with notochord development and those associated with tumour pathology. As has recently been suggested for other cancer types, morphogens and extracellular signals that regulate embryonic notochord development may also play key roles in establishing a microenvironment that promotes chordoma pathogenesis. Schizophrenia is a common psychiatric disease of juvenile to adult onset characterized by positive symptoms such as delusions, hallucinations, thought disorder and disorganized behavior as well as negative symptoms such as blunted emotional response, restriction in fluency and productivity of thought and speech, and impairment in initiation of goal-directed behavior. Its lifetime occurrence is 3.9%, affecting 240 million individuals worldwide as estimated by the World Health Organization. While there are cases where drugs and psychological treatments are effective, the remaining cases are refractory to any form of treatment and its chronic nature requires prolonged care. It leads to major family and social burden and therefore, its underlying mechanism of pathogenesis and effective treatments have been actively sought. The hypofunction of glutamatergic transmission has been implicated in schizophrenia. The first evidence supporting this idea came from a finding that phencyclidine and ketamine, two dissociative anesthetics that induce schizophrenia symptoms in individuals MLN4924 without past history, turned out to be channel blockers of NMDAR. Consistently, animal models of NMDAR hypofunction by genetic down-regulation of NMDAR expression shows traits resembling schizophrenia. Autopsy studies also revealed reduced expression of NMDAR in patients�� brain compared with age-matched controls. These observations lead to an attempt to compensate the reduced NMDAR with positive modulators to treat schizophrenia. NMDAR is composed of a tetrameric combination of NR1, NR2A-D and/or NR3A-B subunits. NR1 is an obligatory subunit required for all NMDAR channels, while NR2 and NR3 add functional diversity observed among different neuronal cell types and developmentally regulated. The majority of neuronal NMDAR are composed of two NR1 and two NR2 while those containing NR3 subunits are limited to particular cell types and ontogenic stages. When NR3 forms a heterooligomer with NR1 and NR2, it works in a dominant-negative fashion to reduce Ca2+-permeability and overall KU-0059436 current. In contrast, when NR3 forms a heterooligomer only with NR1, it forms an excitatory glycinergic receptor, though the presence of synapses that contain such receptors have not been fully demonstrated in native tissue.