Biomedical subjects

Eriko Fujita

Publications and source records attributed to Eriko Fujita.

8 recordsLinked to original sources

PubMed2006

Intracellular distribution of a speech/language disorder associated FOXP2 mutant.

Although a mutation (R553H) in the forkhead box (FOX)P2 gene is associated with speech/language disorder, little is known about the function of FOXP2 or its relevance to this disorder. In the present study, we identify the forkhead nuclear localization domains that contribute to the cellular distribution of FOXP2. Nuclear localization of FOXP2 depended on two distally separated nuclear localization signals in the forkhead domain. A truncated version of FOXP2 lacking the leu-zip, Zn2+ finger, and forkhead domains that was observed in another patient with speech abnormalities demonstrated an aggregated cytoplasmic localization. Furthermore, FOXP2 (R553H) mainly exhibited a cytoplasmic localization despite retaining interactions with nuclear transport proteins (importin alpha and beta). Interestingly, wild type FOXP2 promoted the transport of FOXP2 (R553H) into the nucleus. Mutant and wild type FOXP2 heterodimers in the nucleus or FOXP2 R553H in the cytoplasm may underlie the pathogenesis of the autosomal dominant speech/language disorder.

Amino Acid Sequence↗

PubMed2006

Oligo-astheno-teratozoospermia in mice lacking RA175/TSLC1/SynCAM/IGSF4A, a cell adhesion molecule in the immunoglobulin superfamily.

RA175/TSLC1/SynCAM/IGSF4A (RA175), a member of the immunoglobulin superfamily with Ca2+-independent homophilic trans-cell adhesion activity, participates in synaptic and epithelial cell junctions. To clarify the biological function of RA175, we disrupted the mouse Igsf4a (Ra175/Tslc1/SynCam/Igsf4a Ra175) gene. Male mice lacking both alleles of Ra175 (Ra175-/-) were infertile and showed oligo-astheno-teratozoospermia; almost no mature motile spermatozoa were found in the epididymis. Heterozygous males and females and homozygous null females were fertile and had no overt developmental defects. RA175 was mainly expressed on the cell junction of spermatocytes, elongating and elongated spermatids (steps 9 to 15) in wild-type testes; the RA175 expression was restricted to the distal site (tail side) but not to the proximal site (head side) in elongated spermatids. In Ra175-/- testes, elongated and mature spermatids (steps 13 to 16) were almost undetectable; round spermatids were morphologically normal, but elongating spermatids (steps 9 to 12) failed to mature further and to translocate to the adluminal surface. The remaining elongating spermatids at improper positions were finally phagocytosed by Sertoli cells. Furthermore, undifferentiated and abnormal spermatids exfoliated into the tubular lumen from adluminal surfaces. Thus, RA175-based cell junction is necessary for retaining elongating spermatids in the invagination of Sertoli cells for their maturation and translocation to the adluminal surface for timely release.

Animals↗

PubMed2004

Distribution of RA175/TSLC1/SynCAM, a member of the immunoglobulin superfamily, in the developing nervous system.

RA175 is a new member of the immunoglobulin superfamily with trans interaction activity, and it plays a role as a tumor suppressor in lung carcinoma (TSLC1) and as a cell adhesion molecule promoting the formation of functional synapses (SynCAM). Little is known about the biological function of RA175/TSLC1/SynCAM neural network formation during neurogenesis. We examined the distribution and colocalization of the RA175/TSLC1/SynCAM protein with other members of the immunoglobulin superfamily such as NCAM, L1, and TAG-1 in the mouse developing nervous system. Consistent with the expression of RA175/TSLC1/SynCAM mRNA, the protein was localized in the brain neuroepithelium at embryonic day (E) 9.5, neural crest at E10.5, motor neurons at E10.5, and olfactory epithelium at E16.5. In contrast with its mRNA, the protein was intensely detected on the fasciculated axons in the floor plates, ventral root, and dorsal funiculus in the E10.5-11.5 spinal cord and colocalized with NCAM and L1 on the ventral root and dorsal funiculus and partly colocalized with TAG-1 on the commissural axons and dorsal funiculus. In the E13.5-15.5 brain, RA175/TSLC1/SynCAM colocalized with NCAM and L1 on the developing thalamocortical fibers from the internal capsule (IC) and partly colocalized with TAG-1 on the cortical efferent axons in the intermediate zone (IZ). RA175/TSLC1/SynCAM was localized on the axons of some of the cortical neurons cultured in vitro. Thus, in addition to cell adhesion activity in the neuroepithelium and the synapses, RA175/TSLC1/SynCAM may be involved in neuronal migration, axon growth, pathfinding, and fasciculation on the axons of differentiating neurons.

Animals↗

PubMed2003

Region of caspase-3 activation and programmed cell death in the early development of the mouse forebrain.

Caspase-3-deficient 129/Sv mice show hyperplasia of the brain at embryonic (E) day 10.5-12.5, but caspase-3-deficient C57L/B6 mice do not. We examined the relationship between activation of caspase-3 and programmed cell death (PCD) during forebrain development of various mouse strains (129/Sv, ICR, C57L/B6, and CBA) using terminal deoxytransferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) and immunostaining with antiserum against the caspase-3 (anti-m3D175) cleavage site. A number of anti-m3D175 positive cells and TUNEL positive cells were detected in the ventral side of the forebrain of 129/Sv and ICR mice at E8.5-9 but not in C57L/B6 and CBA mice. Ac-DEVD-MCA cleavage activity, a caspase-3-like activity, also suggests the preferential activation of caspase-3 in the ventral forebrain of ICR mice but not in C57L/B6 mice. Developmental changes of TUNEL and anti-m3D175 reactivities were essentially similar during brain morphogenesis of ICR and 129/Sv mice. The number of TUNEL/anti-m3D175 positive cells decreased in the neuroepithelium of the ventral forebrain at E9.5 before generation of the medial ganglionic eminence (MGE). TUNEL and/or anti-m3D175 reactivity was slightly detectable in the MGE at E10.5, from which neuroprogenitor cells follow a tangential migratory route to the cortex. Activation of caspase-9 was also immunohistochemically detected in the ventral forebrain at E8.5-9, suggesting that activation of caspase-3 and caspase-9 occurs in the PCD of this region. Thus, it is likely that decreased cell death in the ventral forebrain of caspase-3- and caspase-9-deficient 129/Sv mice increases the number of neuroprogenitor cells in the MGE, leading to hyperplasia of the forebrain.

Animals↗

PubMed2003

RA175, which is the mouse ortholog of TSLC1, a tumor suppressor gene in human lung cancer, is a cell adhesion molecule.

RA175, a new immunoglobulin superfamily member, is preferentially expressed during differentiation of P19 embryonic carcinoma (EC) cells induced by retinoic acid. In the present study, we isolated mouse RA175 cDNA in its entirety and showed that RA175 is the mouse ortholog of TSLC1, a tumor suppressor gene in human lung cancer. RA175/TSLC1 was localized in the adherent region of human lung squamous carcinoma cells and in the differentiated P19 EC cells. RA175/TSLC1 showed homophilic trans-interaction activity in a Ca(2+)-independent manner. RA175/TSLC1 was preferentially expressed in the polarized cells lining the lumen of developing mouse lung epithelium. This suggests that RA175/TSLC1 is a cell adhesion molecule that is acting as a tumor suppressor gene in the metastasis of lung tumors. RA175/TSLC1 may be necessary for cells to remain tightly associated in the epithelium, thereby suppressing metastasis.

Animals↗

PubMed2003

Strain-specific caspase-3-dependent programmed cell death in the early developing mouse forebrain.

Caspase-3-deficient 129/Sv mice show hyperplasia of the forebrain at embryonic day (E) 10.5, which suggests that caspase-3-dependent programmed cell death (PCD) plays an essential role in brain morphogenesis prior to neurogenesis. However, little is known about region-specific caspase-3-dependent PCD in the developing forebrain. We examined the PCD region in the early developmental brain at E9.5 by whole mount terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL). In addition to hindbrain, TUNEL-reactivity was detected in the ventral forebrain and in the caudal portion of the front nasal region, just behind the regions expressing fgf-8 and otx-2. It has been shown recently that brain hyperplasia induced by caspase-3-deficiency is mouse strain-dependent; such that brain abnormalities were observed in caspase-3-deficient 129/Sv mice but not in caspase-3-deficient C57BL/6 mice. We examined the caspase-3-dependent PCD in the ventral forebrain of 129/Sv and C57BL/6 mouse embryos (E8.5-9 and E9.5) by double staining of TUNEL and antiserum against the active form of caspase-3 (anti-m3D175). TUNEL/anti-m3D175 reactivity in the ventral forebrain was mouse strain-dependent, such that many TUNEL/anti-m3D175-positive cells were detected in the ventral forebrains of 129/Sv mice, but were not observed in C57BL/6 mice. Thus, it is likely that this region is the site of the strain-specific caspase-3-dependent PCD. A strain-dependent 'modulator' that regulates both caspase-3-dependent and -independent cell death pathways may control PCD in the ventral forebrain at E8.5-9.5.

Animals↗

PubMed2002

Identification of the Tslc1 gene, a mouse orthologue of the human tumor suppressor TSLC1 gene.

We have recently identified the TSLC1 gene as a novel tumor suppressor in human non-small lung cancer on chromosome 11q23.2. TSLC1 encodes a membrane glycoprotein showing significant homology with immunoglobulin superfamily molecules. Here, we report the isolation of a mouse orthologous gene, Tslc1. The Tslc1 cDNA contains a single open reading frame of 1335 bp encoding a putative protein of 445 amino acids, and its expression was detected in all tissues examined. The Tslc1 gene is mapped on mouse chromosome 9, a synteny of human chromosome 11q, and is composed of ten exons, the exon-intron junctions being highly conserved between human and mouse. The predicted amino acids of mouse Tslc1 display 98% identity with that of human TSLC1. Furthermore, data base analysis indicates that the amino acid sequences corresponding to the cytoplasmic domain of Tslc1 are identical in five mammals and highly conserved in vertebrates, suggesting an important role of Tslc1 in normal cell-cell interaction.

Amino Acid Sequence↗

PubMed2002

Polyglutamine aggregates stimulate ER stress signals and caspase-12 activation.

Accumulation of unfolded and malfolded proteins causes endoplasmic reticulum (ER) stress, stimulating unfolded protein response (UPR) and c-Jun N-terminal kinase (JNK) activation and activating caspase-12 located on the ER. Little is known about the relationship between the ER stress and polyglutamine [poly(Q)] aggregates. Poly(Q)72 repeats [poly(Q)(72)] induced the stimulation of ER stress signals such as JNK activation, upregulation of Grp78/Bip and caspase-12 activation in C2C5 cells. We prepared antiserum against the cleavage site of mouse caspase-12 at D(318) (anti-m12D318), and showed that poly(Q)(72) with perinuclear aggregates, cytoplasmic inclusions and nuclear inclusions stimulated JNK activation and anti-m12D318 immunoreactivity, but poly(Q)(72) with dispersed aggregates and small nuclear aggregates showed a significantly less effect. Poly(Q)(72) and poly(Q)(11) dispersed in cytoplasm did not. Anti-m12D318-positive cells showed apoptotic features. Unlike anti-m8D387 immunoreactivity, the anti-m12D318 immunoreactivity was not coaggregated with poly(Q). Ac-IETD-fmk (caspase-8 inhibitor) and Ac-DEVD-CHO (caspase-3 inhibitor) did not prevent the anti-m12D318 immunoreactivity induced by poly(Q)(72) aggregates. Anti-m12D318 immunoreactivity was detected in caspase-8(-/-) and caspase-3(-/-) mouse embryonic fibroblasts expressing poly(Q)(72) aggregates. Thus, caspase-12 was activated by poly(Q)(72) aggregates via a pathway independent of caspase-8 and caspase-3 activation, and caspase-12 activation was closely associated with poly(Q) aggregate-mediated cell death. Stimulation of ER stress signals may be involved in the pathogenesis of neurodegenerative disorders with poly(Q) expansion.

Animals↗