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At least 901 records · Page 50Linked to original sources
PubMed2005

Neuronal subtype-specific genes that control corticospinal motor neuron development in vivo.

Within the vertebrate nervous system, the presence of many different lineages of neurons and glia complicates the molecular characterization of single neuronal populations. In order to elucidate molecular mechanisms underlying the specification and development of corticospinal motor neurons (CSMN), we purified CSMN at distinct stages of development in vivo and compared their gene expression to two other pure populations of cortical projection neurons: callosal projection neurons and corticotectal projection neurons. We found genes that are potentially instructive for CSMN development, as well as genes that are excluded from CSMN and are restricted to other populations of neurons, even within the same cortical layer. Loss-of-function experiments in null mutant mice for Ctip2 (also known as Bcl11b), one of the newly characterized genes, demonstrate that it plays a critical role in the development of CSMN axonal projections to the spinal cord in vivo, confirming that we identified central genetic determinants of the CSMN population.

Animals↗
PubMed2004

Expression profiling in spinal muscular atrophy reveals an RNA binding protein deficit.

Spinal muscular atrophy is a common neuromuscular disorder caused by deletions or mutations within the survival motor neuron gene. The reason for specific motor neuron loss within the disease is still unclear. Expression profiling has been carried out in two models of spinal muscular atrophy; the heterozygote mouse model and human primary muscle cultures from a spinal muscular atrophy patient. A group of RNA binding proteins are up-regulated in spinal muscular atrophy motor neurons. One such protein, BRUNOL3, is highly expressed within spinal cord and muscle and also at the same developmental stage as survival motor neuron. The differential expression of Brunol3 has been confirmed with real-time RT-PCR in spinal cord and muscle of three different models of spinal muscular atrophy. BRUNOL3 has been shown to co-localise with survival motor neuron in the nuclei of neuronal cells and to co-immunoprecipitate with Smn in mouse brain. This is the first time that a link has been established between RNA binding proteins and survival motor neuron within motor neurons.

Adolescent↗
PubMed2005

ICAM-5 (telencephalin) gene expression in head and neck squamous carcinoma tumorigenesis and perineural invasion!

ICAM-5 (telencephalin) is an intercellular adhesion molecule reported to be expressed only in the somatodendritic membrane of telencephalic neurons. We recently identified high ICAM-5 expression in a cDNA array study of head and neck neoplasms with a propensity for perineural invasion. To determine the association of this gene in tumorigenesis and perineural invasion, we analyzed the expression and functional status of ICAM-5 mRNA transcripts in 30 different human cancer cell lines and 25 head and neck squamous carcinoma specimens by reverse-transcriptase polymerase chain reaction (cell lines and specimens) and in vitro functional assays (cell lines). ICAM-5 transcripts were detected in 28 (93%) of 30 cell lines derived from primary head and neck, colon, thyroid, cervical, pancreatic, skin, and adenoid cystic carcinomas. In cell lines, small interfering RNA blocked ICAM-5 expression and inhibited cell proliferation. Treatment with the phosphatidylinositol 3'-kinase (PBK) inhibitor LY294002 resulted in ICAM-5 down-regulation. In tissue specimens, none of the 25 histologically normal oral mucosal specimens had detectable ICAM-5 level, whereas 16 (64%) of the 25 matched primary squamous carcinomas showed expression. Carcinoma specimens high ICAM-5 expression had a high incidence of perineural invasion. Our study indicates that ICAM-5 may play a role in tumorigenesis and perineural invasion, most likely through the P13K/Akt-signaling pathway.

Adult↗
PubMed2005

Variations in myelin and oligodendrocyte-related gene expression across multiple brain regions in schizophrenia: a gene ontology study.

Large-scale gene expression studies in schizophrenia (SZ) have generally focused on the dorsolateral prefrontal cortex. Studies of other brain regions have been less frequent and have rarely been performed in the same subjects. We analyzed postmortem gene expression in multiple cortical regions (Brodmann areas 8, 10, 44, 46, 23/31, 24/32, 20, 21, 22, 36/28, 7 and 17, respectively) as well as in the hippocampus, caudate nucleus, and putamen of 13 SZ and 13 control subjects using Affymetrix GeneChip(R) microarrays. The superior temporal cortex (BA22) and cingulate cortices (BA24/32, 23/31) of subjects with SZ demonstrated more profound alterations of gene expression than other brain regions compared to controls [Katsel, P., Davis, K.L., Gorman, J.M., Haroutunian, V., in press. Variations in differential gene expression patterns across multiple brain regions in schizophrenia. Schizophr. Res.]. Functional categorization of genes whose expression was altered revealed multiple gene ontology classes that included oligodendrocyte/myelin-related genes. These myelin-related ontologies were among the top scored categories in temporal and cingulate gyri and in the hippocampus relative to other brain regions. The most altered transcripts in SZ were those encoding for proteins involved in determination of glial differentiation, myelin structure and adhesion proteins participating in axoglial contacts. Hierarchical clustering demonstrated that these myelin-related gene expression abnormalities in SZ were most pronounced in the hippocampus, superior temporal and cingulate cortices. The high representation of abnormally expressed oligodendrocyte/myelin genes in brain regions with the largest numbers of abnormally expressed genes in SZ confirmed their involvement in the disease process and suggested that the integrity of axon-myelin interaction may be impaired in SZ.

Aged↗
PubMed2000

PA-FABP, a novel marker of human epidermal transit amplifying cells revealed by 2D protein gel electrophoresis and cDNA array hybridisation.

Human epidermal stem cells express higher levels of beta1 integrins than their more differentiated daughters, transit amplifying cells. In a search for additional stem and transit cell markers we used proteomics and differential cDNA hybridisation to compare keratinocytes fractionated on the basis of beta1 integrin expression. There were remarkably few differences between the two populations and none of the RNAs differed in abundance by more than 2-fold. Nevertheless, proteomics revealed upregulated expression of epidermal fatty acid binding protein (PA-FABP, also known as E-FABP), Annexin II and two keratin related proteins in the transit population. An unknown high molecular mass protein was upregulated in the stem cell population. The upregulation of PA-FABP was confirmed by Northern blotting and conventional and whole mount labelling of human epidermis. We conclude that PA-FABP is a novel marker of epidermal transit amplifying cells.

3T3 Cells↗
PubMed2003

Epidermal growth factor receptor expression in follicular dendritic cells: a shared feature of follicular dendritic cell sarcoma and Castleman's disease.

The factors regulating the growth of follicular dendritic cell (FDC) sarcoma are currently unknown. Using cDNA microarray analysis, we found that the epidermal growth factor receptor (EGFR) is expressed in FDC sarcoma. We immunohistochemically examined the expression of EGFR in a larger series of FDC sarcomas and in nonneoplastic FDCs. This included 8 cases of FDC sarcoma, 12 cases of hyaline vascular Castleman's disease (CD), 5 cases of human herpesvirus 8 (HHV8)-positive plasma cell CD, 7 cases of HHV8-negative plasma cell CD, 13 cases of reactive lymph nodes, 3 cases of reactive tonsils, 10 cases of follicular lymphoma, 6 cases of nodular mantle cell lymphoma, and 6 cases of angioimmunoblastic T-cell lymphoma. EGFR was expressed in tumor cells in 7 of 8 cases (88%) of FDC sarcoma (strongly in 4 cases and moderately in 3 cases). The single EGFR-negative case had an anaplastic appearance and a more aggressive clinical behavior. EGFR was also expressed by FDC in all types of CD (strongly in 4 cases, moderately in 16 cases, and weakly in 4 cases). Immunostaining results were negative or only weakly positive for EGFR in FDC of reactive lymph nodes and tonsils, and in the FDC networks of follicular lymphoma, mantle cell lymphoma, and angioimmunoblastic lymphoma. The up-regulation of EGFR in FDC of CD was paralleled by an increase in EGFR expression in the surrounding perifollicular fibroblastic reticulum cells suggesting coordinate regulation. These findings identify a differentially expressed growth regulatory receptor common to both FDC sarcoma and CD, identifying a target for possible therapy in unresectable or refractory cases.

Adult↗
PubMed2001

Microarray identification of FMRP-associated brain mRNAs and altered mRNA translational profiles in fragile X syndrome.

Fragile X syndrome results from the absence of the RNA binding FMR protein. Here, mRNA was coimmunoprecipitated with the FMRP ribonucleoprotein complex and used to interrogate microarrays. We identified 432 associated mRNAs from mouse brain. Quantitative RT-PCR confirmed some to be >60-fold enriched in the immunoprecipitant. In parallel studies, mRNAs from polyribosomes of fragile X cells were used to probe microarrays. Despite equivalent cytoplasmic abundance, 251 mRNAs had an abnormal polyribosome profile in the absence of FMRP. Although this represents <2% of the total messages, 50% of the coimmunoprecipitated mRNAs with expressed human orthologs were found in this group. Nearly 70% of those transcripts found in both studies contain a G quartet structure, demonstrated as an in vitro FMRP target. We conclude that translational dysregulation of mRNAs normally associated with FMRP may be the proximal cause of fragile X syndrome, and we identify candidate genes relevant to this phenotype.

Amino Acid Sequence↗
PubMed2001

Differential expression of adipose- and heart-type fatty acid binding proteins in hibernating ground squirrels.

The up-regulation of heart- and adipose-type fatty acid binding proteins (H-FABPs and A-FABPs) was detected during hibernation in brown adipose tissue (BAT) of 13-lined ground squirrels, Spermophilus tridecemlineatus, using a commercial rat cDNA array. Full length cDNAs encoding H-FABPs and A-FABPs were subsequently retrieved from a BAT cDNA library. These cDNAs were used to probe Northern blots of total RNA from tissues of euthermic versus hibernating ground squirrels. H-FABP mRNA transcripts increased in BAT, skeletal muscle and heart of hibernating animals whereas A-FABP transcripts, which are normally expressed exclusively in adipose tissue, increased in both BAT and heart during torpor. It is proposed that the increased expression of H-FABPs and A-FABPs during hibernation accelerates the rate at which fatty acids can be transported to the mitochondria for oxidization, particularly in support of the huge increase in thermogenesis by BAT and rapid increase in heart rate that are required during arousal from torpor. Comparison of the deduced polypeptide sequence of ground squirrel H-FABP with that from other mammals also revealed three unique amino acid differences which may be important for protein function at low body temperatures during hibernation.

Adipose Tissue↗
PubMed2003

Sexually dimorphic gene expression in mouse brain precedes gonadal differentiation.

The classic view of brain sexual differentiation and behavior is that gonadal steroid hormones act directly to promote sex differences in neural and behavioral development. In particular, the actions of testosterone and its metabolites induce a masculine pattern of brain development, while inhibiting feminine neural and behavioral patterns of differentiation. However, recent evidence indicates that gonadal hormones may not solely be responsible for sex differences in brain development and behavior between males and females. Here we examine an alternative hypothesis that genes, by directly inducing sexually dimorphic patterns of neural development, can influence the sexual differences between male and female brains. Using microarrays and RT-PCR, we have detected over 50 candidate genes for differential sex expression, and confirmed at least seven murine genes which show differential expression between the developing brains of male and female mice at stage 10.5 days post coitum (dpc), before any gonadal hormone influence. The identification of genes differentially expressed between male and female brains prior to gonadal formation suggests that genetic factors may have roles in influencing brain sexual differentiation.

Animals↗
PubMed2001

Genes in drug abuse.

Because of the genome projects it will be possible to identify the changes in gene expression that are associated with drug abuse. The ultimate goal will be to determine the role and significance of the gene products. To date about 100 genes have been found with altered expression after administration of drugs. The development of new technologies such as microarrays will greatly facilitate finding such changes in expression. The rate at which levels of some gene products change is compatible with the time course of development of dependence in animals, but we must be able to establish a cause-effect relationship between genes and drug abuse, which this will be difficult. The product of the novel cocaine and amphetamine regulated transcript (CART) gene is a useful example where a gene product has been associated with drug abuse. CART was identified as an mRNA that changed in response to psychostimulant drug administration and injection of CART peptides into the ventral tegmental area produces psychostimulant-like effects. Definitive evidence, if obtainable, that specific genes are responsible for vulnerability to drug abuse could have dramatic effects on public health policy.

Animals↗
PubMed2004

Characterisation of DRASIC in the mouse inner ear.

Within the cochlea, the hair cells detect sound waves and transduce them into receptor potential. The molecular architecture of the highly specialised cochlea is complex and until recently little was known about the molecular interactions which underlie its function. It is now clear that the coordinated expression and interplay of hundreds of genes and the integrity of cochlear cells regulate this function. It was hypothesised that transcripts expressed highly or specifically in the cochlea are likely to have important roles in normal hearing. Microarray analyses of the Soares NMIE library, consisting of 1536 cDNA clones isolated from the mouse inner ear, suggested that the expression of the mechanoreceptor DRASIC was enriched in the cochlea compared to other tissues. This amiloride-sensitive ion channel is a member of the DEG/ENaC superfamily and a potential candidate for the unidentified mechanoelectrical transduction channel of the sensory hair cells of the cochlea. The cochlear-enriched expression of amiloride-sensitive cation channel 3 (ACCN3) was confirmed by quantitative real-time polymerase chain reaction. Using in situ hybridisation and immunofluorescence, DRASIC expression was localised to the cells and neural fibre region of the spiral ganglion. DRASIC protein was also detected in cells of the organ of Corti. DRASIC may be present in cochlear hair cells as the ACCN3 transcript was shown to be expressed in immortalised cell lines that exhibit characteristics of hair cells. The normal mouse ACCN3 cDNA and an alternatively spliced transcript were elucidated by reverse transcription polymerase chain reaction from mouse inner ear RNA. This transcript may represent a new protein isoform with an as yet unknown function. A DRASIC knockout mouse model was tested for a hearing loss phenotype and was found to have normal hearing at 2 months of age but appeared to develop hearing loss early in life. The human homologue of ACCN3, acid-sensing ion channel 3, maps to the same chromosomal region as the autosomal recessive hearing loss locus DFNB13. However, we did not detect mutations in this gene in a family with DFNB13 hearing loss.

Acid Sensing Ion Channels↗
PubMed2002

A catalytic antioxidant (AEOL 10150) attenuates expression of inflammatory genes in stroke.

Oxidative stress is a major source of injury from cerebral ischemia and reperfusion. We hypothesized that a catalytic antioxidant AEOL 10150 [manganese (III) meso-tetrakis (di-N-ethylimidazole) porphyrin] would attenuate changes in brain gene expression in a mouse model of transient middle cerebral artery occlusion (MCAO). C57BL/6J mice were subjected to either sham surgery or 60 min of right MCAO. AEOL 10150 or phosphate-buffered saline was given intravenously 5 min after onset of reperfusion (n = 6 per group). Six hours later, parenchyma within the MCA distribution was harvested. RNA from the six brains in each group was pooled and mRNA expression determined using an Affymetrix murine MG_U74A v. 2.0 expression microarray. Each experiment was performed three times. The largest changes in expression occurred in stress response and inflammatory genes such as heat shock protein, interleukin-6, and macrophage inflammatory protein-2. Treatment with AEOL 10150 attenuated only the increase in expression of inflammatory genes. This suggests that AEOL 10150 protects brain by attenuating the immune response to ischemia and reperfusion.

Animals↗
PubMed2001

EGR2 mutations in inherited neuropathies dominant-negatively inhibit myelin gene expression.

The identification of EGR2 mutations in patients with neuropathies and the phenotype Egr2/Krox20(-/-) have demonstrated that the Egr2 transcription factor is critical for peripheral nerve myelination. However, the mechanism by which these mutations cause disease remains unclear, as most patients present with disease in the heterozygous state, whereas Egr2(+/-) mice are phenotypically normal. To understand the effect of aberrant Egr2 activity on Schwann cell gene expression, we performed microarray expression profiling to identify genes regulated by Egr2 in Schwann cells. These include genes encoding myelin proteins and enzymes required for synthesis of normal myelin lipids. Using these newly identified targets, we have shown that neuropathy-associated EGR2 mutants dominant-negatively inhibit wild-type Egr2-mediated expression of essential myelin genes to levels sufficiently low to result in the abnormal myelination observed in these patients.

Animals↗
PubMed2002

Identification of a novel microtubule-associated protein that regulates microtubule organization and cytokinesis by using a GFP-screening strategy.

Microtubules play critical roles in a variety of cell processes, including mitosis, organelle transport, adhesion and migration, and the maintenance of cell polarity. Microtubule-associated proteins (MAPs) regulate the dynamic organization and stability of microtubules, often through either cell-specific or cell division stage-specific interactions. To identify novel cytoskeletal-associated proteins and peptides that regulate microtubules and other cytoskeletal and adhesive structures, we have developed a GFP cDNA screening strategy based on identifying gene products that localize to these structures. Using this approach, we have identified a novel MAP, GLFND, that shows homology to the Opitz syndrome gene product [6], localizes to a subpopulation of microtubules that are acetylated, and protects microtubules from depolymerization with nocodazole. Expression of an N-terminal deletion binds microtubules but alters their organization. During the cell cycle, GLFND dissociates from microtubules at the beginning of mitosis and then reassociates at cytokinesis. Furthermore, ectopic expression of GLFND inhibits cell division and cytokinesis in CHO cells. These observations make GLFND unique among MAPs characterized thus far.

Animals↗
PubMed1999

Options available--from start to finish--for obtaining expression data by microarray.

The excitement surrounding microarray technology has been tempered by the limited ability of the general biomedical research community to gain access to it. Given the hardware required for exploitation of the technology is becoming increasingly available, it is an appropriate moment to review options, be they commercially or publically available. Here, we provide a snapshot of the rapidly changing field of microarray-based RNA expression analysis and consider the components and procedures for putting together a complete system.

Animals↗
PubMed2005

Gene expression profiling in the hippocampus of learned helpless and nonhelpless rats.

In the learned helplessness (LH) animal model of depression, failure to attempt escape from avoidable environmental stress, LH, indicates behavioral despair, whereas nonhelpless (NH) behavior reflects behavioral resilience to the effects of environmental stress. Comparing hippocampal gene expression with large-scale oligonucleotide microarrays, we found that stress-resilient (NH) rats, although behaviorally indistinguishable from controls, showed a distinct gene expression profile compared to LH, sham stressed, and naïve control animals. Genes that were confirmed as differentially expressed in the NH group by quantitative PCR strongly correlated in their levels of expression across all four animal groups. Differential expression could not be confirmed at the protein level. We identified several shared degenerate sequence motifs in the 3' untranslated region (3'UTR) of differentially expressed genes that could be a factor in this tight correlation of expression levels among differentially expressed genes.

Adaptor Proteins, Vesicular Transport↗
PubMed2001

Gene expression profiles during long-term memory consolidation.

Changes in gene expression have been postulated to occur during long-term memory (LTM). We used high-density cDNA microarrays to assess changes in gene expression 24 h after rabbit eye blink conditioning. Paired animals were presented with a 400 ms, 1000 Hz, 82 dB tone conditioned stimulus that coterminated with a 100 ms, 60 Hz, 2 mA electrical pulse unconditioned stimulus. Unpaired animals received the same conditioned and unconditioned stimuli but presented in an explicitly unpaired manner. Differences in expression levels between paired and unpaired animals in the hippocampus and cerebellar lobule HVI, two regions activated during eye blink conditioning, indicated the involvement of novel genes as well as the participation of previously implicated genes. Patterns of gene expression were validated by in situ hybridization. Surprisingly, the data suggest that an underlying mechanism of LTM involves widespread decreased, rather than increased, gene expression. These results demonstrate the feasibility and utility of a cDNA microarray system as a tool for dissecting the molecular mechanisms of associative memory.

Animals↗