Disrupted-In-Schizophrenia 1 (DISC1) was identified as a novel gene disrupted by a (1;11)(q42.1;q14.3) translocation that segregated with schizophrenia in a Scottish family. Predicted DISC1 product has no significant homology to other known proteins. Here, we demonstrated the existence of DISC1 protein and identified fasciculation and elongation protein zeta-1 (FEZ1) as an interacting partner of DISC1 by a yeast two-hybrid study. FEZ1 and its nematode homolog are reported to represent a new protein family involved in axonal outgrowth and fasciculation. In cultured hippocampal neurons, DISC1 and FEZ1 colocalized in growth cones. Interactions of these proteins were associated with F-actin. In the course of neuronal differentiation of PC12 cells, upregulation of DISC1/FEZ1 interaction was observed as along with enhanced extension of neurites by overexpression of DISC1. The present study shows that DISC1 participates in neurite outgrowth through its interaction with FEZ1. Recent studies have provided reliable evidence that schizophrenia is a neurodevelopmental disorder. As there is a high level of DISC1 expression in developing rat brain, dysfunction of DISC1 may confer susceptibility to psychiatric illnesses through abnormal development of the nervous system.

Urinary excretion of human liver-type fatty acid-binding protein (hL-FABP

No abstract

A functional cDNA clone for a third isoform of the mouse prostaglandin-E-receptor EP, subtype, derived by alternative RNA splicing, named the EP,, receptor, was obtained in addition to those for the two other isoforms, EP,,, and EP,,. The three isoforms are only different in the amino acid sequence of the putative cytoplasmic carboxy-terminal tail. When expressed, EP,,. shows identical ligand-binding properties to these of the other isoforms. The EP,-selective agonist, M&B 28767, increased the basal CAMP level and inhibited the forskolin-induced increase in the CAMP level in EP,,., while it decreased both the basal and forskolin-elevated CAMP levels in EP,, and EP, . The M&B 28767-stimulated GTPase activity consisted of pertussis-toxin-sensi tive and cholera-toxinsensitive portions in the EP,,-expressing cell membrane, suggested that EP,,, is coupled to both guanine nucleotide-binding inhibitory and stimulatory proteins. These results indicate that EP,,. is coupled to both stimulation and inhibition of adenylate cyclase, but that EP3, and EP,, are exclusively coupled to inhibition of adenylate cyclase. Thus, alternative splicing produces a third isoform with a different carboxy-terminal tail, which differs from the other two isoforms in the specificity of coupling to a signal-transduction pathway.Prostaglandin (PG) E, exhibits a broad range or biological actions in diverse tissues through specific receptors on plasma membranes for maintenance of local homeostasis in the body [l, 21. In the process of the cloning of the two EP, isoforms, we obtained a third isoform, which is also produced through alternative splicing and differs only in the carboxy-terminal tail from the other two isoforms. We now report the cloning and expression of the third EP, isoform. We show that this receptor is coupled to both stimulation and inhibition of adenylate cyclase. This finding will be of help in understanding the diversity of the actions of P G b , and shows the importance of thc carboxy-terminal tail in the specificity of coupling to a second-messenger system.

No abstract

Recently, endoplasmic reticulum (ER) dysfunction has been implicated in neuronal death in patients with Alzheimer's disease. Treatment of human neuroblastoma cells with ER stress inducers causes apoptotic death. We confirmed that ER stress inducers specifically targeted the ER to cause apoptotic morphological changes. We also found that caspase-3, and not caspase-9 (a known mitochondrial apoptotic mediator), was mainly activated by ER stress. We generated the neuroblastoma cells that stably expressed caspase-12 and analyzed its influence on caspase-3 activation and vulnerability to ER stress. Cells expressing caspase-12 were more vulnerable to ER stress than cells expressing the empty vector, concomitant with increased activation of caspase-3. These findings suggested that activation of ER-resident caspase-12 indirectly activates cytoplasmic caspase-3 and might be important in ER stress-induced neuronal apoptosis.

No abstract

The aberrant splicing isoform (PS2V), generated by exon 5 skipping of the Presenilin-2 (PS2) gene transcript, is a diagnostic feature of sporadic Alzheimer's disease (AD). We found PS2V is hypoxia-inducible in human neuroblastoma SK-N-SH cells. We purified a responsible trans-acting factor based on its binding to an exon 5 fragment. The factor was identified as the high mobility group A1a protein (HMGA1a; formerly HMG-I). HMGA1a bound to a specific sequence on exon 5, located upstream of the 5 0 splice site. HMGA1a expression was induced by hypoxia and the protein was accumulated in the nuclear speckles with the endogenous splicing factor SC35. Overexpression of HMGA1a generated PS2V, but PS2V was repressed by cotransfection with the U1 snRNP 70K protein that has a strong affinity to HMGA1a. HMGA1a could interfere with U1 snRNP binding to the 5 0 splice site and caused exon 5 skipping. HMGA1a levels were significantly increased in the brain tissue from sporadic AD patients. We propose a novel mechanism of sporadic AD that involves HMGA1a-induced aberrant splicing of PS2 premRNA in the absence of any mutations.