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At least 1,153 records · Page 64Linked to original sources
PubMed1999

Fjx1, the murine homologue of the Drosophila four-jointed gene, codes for a putative secreted protein expressed in restricted domains of the developing and adult brain.

The Drosophila gene four jointed (fj) codes for a secreted or cell surface protein important for growth and differentiation of legs and wings and for proper development of the eyes. Here we report the cloning of the mouse four-jointed gene (fjx1) and its pattern of expression in the brain during embryogenesis and in the adult. In the neural plate, fjx1 is expressed in the presumptive forebrain and midbrain, and in rhombomere 4, however a small rostral/medial area of the forebrain primordium is devoid of expression. Expression of fjx1 in the neural tube can be divided into three phases. (1) In the embryonic brain fjx1 is expressed in two patches of neuroepithelium: in the midbrain tectum and the telencephalic vesicles. (2) In fetal and early postnatal brain fjx1 is expressed mainly by the primordia of layered telencephalic structures: cortex (ventricular layer and cortical plate), olfactory bulb (subependymal layer and in the mitral cell layer). In addition expression is observed in the superior colliculus. (3) In the adult, fjx1 is expressed by neurones evenly distributed in the telencephalon (isocortex, striatum, hippocampus, olfactory bulb, piriform cortex), in the Purkinje cell layer of the cerebellum, and numerous medullary nuclei. In the embryo, strong expression can further be seen in the apical ectodermal ridge of fore- and hindlimbs and in the ectoderm of the branchial arches.

Amino Acid Sequence↗
PubMed2000

Role of maternal biochemistry in fetal brain development: effect of maternal thyroidectomy on behaviour and biogenic amine metabolism in rat progeny.

Few studies have addressed the role of biochemicals of maternal origin on fetal neurodevelopment and behavioural outcome. Thyroid deficiency in the thyroidectomized pregnant rat provides an excellent model to study fetal effects of maternal chemistry, as this condition is known to be associated with deficits in motor and cognitive behaviour in human offspring. Based on evidence that thyroid hormone of maternal origin may be an important determinant in regulating these behaviours, we assessed neurobehaviours and regional brain biogenic amine levels in offspring of rats thyroidectomized (Tx) prior to conception. Cross-fostering techniques were used to isolate fetal effects of maternal thyroid deficiency from possible neonatal effects during nursing by thyroid-deficient dams. The progeny of Tx dams showed significant deficits in maze learning, were less cautious in emotionality testing, and were more active in open-field exploration. Tx females appeared to be more vulnerable to the effects on learning. Learning in Tx males was only slightly impaired. Serotonin and dopamine metabolism was also affected in a brain region-specific manner in Tx progeny. Levels of 5-HIAA were reduced in the olfactory tubercle and cortex. HVA levels were lower in olfactory tubercle, but were elevated in the hippocampus. As these neurotransmitters play a functional role in activity, mood and learning, the findings may be pertinent to the observed behavioural impairments. The results are consistent with the hypothesis that an adequate in utero thyroid hormone environment may be essential for early fetal neurodevelopment even if the fetus is euthyroid.

Journal Article↗
PubMed2000

Isozyme pattern of glycogen phosphorylase in the rat nervous system and rat astroglia-rich primary cultures: electrophoretic and polymerase chain reaction studies.

Of the three isozymes of glycogen phosphorylase (GP) known, the brain (B) and muscle (M) isoforms have been reported to occur in brain. We investigated the regional and cellular occurrence of the three isozymes in various parts of the rat nervous system, fetal brain and astroglia-rich primary cultures by means of electrophoresis of native proteins with subsequent activity stain and by reverse transcriptase polymerase chain reaction. In the cortex, cerebellum, olfactory bulb, brainstem, spinal cord and dorsal root ganglia, both mRNA and enzyme protein were found for the B and M isozymes. In addition, the liver (L) isoform mRNA was detected in fetal brain and cultured astrocytes. Our studies indicate that there is no regional difference in distribution pattern between brain regions, spinal cord and dorsal root ganglia. In immature brain and cultured glial cells, the additional presence of the L isozyme is possible. These results support the idea that astrocytes express two or even three GP isozymes simultaneously.

Animals↗
PubMed1992

Nested expression domains of four homeobox genes in developing rostral brain.

Insight into the genetic control of the identity of specific regions along the body axis of vertebrates has resulted primarily from the study of vertebrate homologues of regulatory genes operating in the Drosophila trunk, but little is known about the development of most anterior regions of the body either in flies or vertebrates. Three Drosophila genes have been identified that are important in controlling the development of the head, two of which, empty spiracles and orthodenticle, have been cloned and shown to contain a homeobox. We previously cloned and characterized Emx1 and Emx2, two mouse genes related to empty spiracles that are expressed in restricted regions of the developing forebrain, including the presumptive cerebral cortex and olfactory bulbs. Here we report the identification of Otx1 and Otx2, which are related to orthodenticle. We have compared the expression domains of the four genes in the developing rostral brain of mouse embryos at a developmental stage, day 10 post coitum, when they are all expressed. Otx2 is expressed in every dorsal and most ventral regions of telencephalon, diencephalon and mesencephalon. The Otx1 expression domain is similar to that of Otx2, but contained within it. The Emx2 expression domain is comprised of dorsal telencephalon and small diencephalic regions, both dorsally and ventrally. Finally, Emx1 expression is exclusively confined to the dorsal telencephalon. Thus at the time when regional specification of major brain regions takes place, the expression domains of the four genes seem to be continuous regions contained within each other in the sequence Emx1 less than Emx2 less than Otx1 less than Otx2.

Amino Acid Sequence↗
PubMed2006

Neuronal survival depends on EGFR signaling in cortical but not midbrain astrocytes.

Mice lacking epidermal growth factor receptor (EGFR) develop a neurodegeneration of unknown etiology affecting exclusively the frontal cortex and olfactory bulbs. Here, we show that EGFR signaling controls cortical degeneration by regulating cortical astrocyte apoptosis. Whereas EGFR(-/-) midbrain astrocytes are unaffected, mutant cortical astrocytes display increased apoptosis mediated by an Akt-caspase-dependent mechanism and are unable to support neuronal survival. The expression of many neurotrophic factors is unaltered in EGFR(-/-) cortical astrocytes suggesting that neuronal loss occurs as a consequence of increased astrocyte apoptosis rather than impaired secretion of trophic factors. Neuron-specific expression of activated Ras can compensate for the deficiency of EGFR(-/-) cortical astrocytes and prevent neuronal death. These results identify two functionally distinct astrocyte populations, which differentially depend on EGFR signaling for their survival and also for their ability to support neuronal survival. These spatial differences in astrocyte composition provide a mechanism for the region-specific neurodegeneration in EGFR(-/-) mice.

Animals↗
PubMed2003

alpha 1d Adrenoceptor signaling is required for stimulus induced locomotor activity.

alpha 1 Adrenergic receptors mediate a variety of physiological responses and have been well studied in the cardiovascular and peripheral nervous system. However, their role in the central nervous system remains ill defined because of the lack of highly specific ligands to the alpha1 receptor subtypes. Here, we have employed gene targeting to elucidate the role of alpha 1d receptors in vivo. In addition to disrupting function, the insertion of the lacZ gene into the alpha 1d receptor locus enabled the specific identification of cells expressing the alpha 1d gene. These cells are localized in the cortex, hippocampus, olfactory bulb, dorsal geniculate and ventral posterolateral nuclei of the thalamus. Behaviorally, the alpha 1d(-/-) mice show normal locomotor activity during the subjective day, or resting phase of their cycle. However, during subjective night, or active phase, wheel-running activity is significantly reduced in mutant mice. Furthermore, these mice show a reduction in exploratory rearing behavior in a novel cage environment. Lastly, alpha 1d(-/-) mice show reduced hyperlocomotion after acute amphetamine administration. Together, these data reveal the functional importance of alpha 1d adrenoceptors in mediating a variety of stimulus-induced changes in locomotor behaviors. While the sensitivity of noradrenergic neurons to environmental stimuli has been well documented, our data demonstrate that at least some of these post-synaptic responses are mediated by alpha 1d adrenergic receptors.

Alleles↗
PubMed2004

Expression of disrupted in schizophrenia 1 (DISC1) protein in the adult and developing mouse brain indicates its role in neurodevelopment.

Disrupted in Schizophrenia 1 (DISC1) was identified as a potential susceptibility gene for schizophrenia due to its disruption by a balanced t(1;11) (q42;q14) translocation, which has been shown to cosegregate with major psychiatric disease in a large Scottish family. We have recently presented evidence that DISC1 exists in a neurodevelopmentally regulated protein complex with Nudel. In this study, we report the protein expression profile of DISC1 in the adult and developing mouse brain utilizing immunohistochemistry and quantitative Western blot. In the adult mouse brain, DISC1 is expressed in neurons within various brain areas including the olfactory bulb, cortex, hippocampus, hypothalamus, cerebellum and brain stem. During development, DISC1 protein is detected at all stages, from E10 to 6 months old, with two significant peaks of protein expression of a DISC1 isoform at E13.5 and P35. Interestingly, these time points correspond to critical stages during mouse development, the active neurogenesis period in the developing brain and the period of puberty. Together, these results suggest that DISC1 may play a critical role in brain development, consistent with the neurodevelopmental hypothesis of the etiology of schizophrenia.

Animals↗
PubMed2004

A novel neuronal-specific splice variant of Type I phosphatidylinositol 4-phosphate 5-kinase isoform gamma.

Type I PIPkins (phosphatidylinositol 4-phosphate 5-kinases) are the enzymes that catalyse the major cellular route of synthesis of PtdIns(4,5) P2, and three isoforms (alpha, beta and gamma) with several splice variants have been found to date. In the present paper, we describe the discovery of a novel splice variant of the gamma isoform, which we call PIPkin Igammac, and which is characterized by the inclusion of a 26-amino-acid insert near the C-terminus. Its transcript appears to be selectively expressed in brain, where it locates in the neurons of restricted regions, such as cerebellum, hippocampus, cortex and olfactory bulb, as indicated by in situ hybridization studies. Overexpression of two different catalytically inactive constructs of PIPkin Igammac in rat cerebellar granule cells causes a progressive loss of their neuronal processes, whereas equivalent kinase-dead versions of PIPkin Igammaa did not induce any such effect, suggesting the possible existence of a specific PtdIns(4,5) P2 pool synthesized by PIPkin Igammac, which is involved in the maintenance of some neuronal cellular processes.

Alternative Splicing↗
PubMed1998

Expression of the mitotic motor protein CHO1/MKLP1 in postmitotic neurons.

The kinesin-related motor protein CHO1/MKLP1 was initially thought to be expressed only in mitotic cells, where it presumably transports oppositely oriented microtubules relative to one another in the spindle mid-zone. We have recently shown that CHO1/MKLP1 is also expressed in cultured neuronal cells, where it is enriched in developing dendrites [Sharp et al. (1997a) J. Cell Biol., 138, 833-843]. The putative function of CHO1/MKLP1 in these postmitotic cells is to intercalate minus-end-distal microtubules among oppositely oriented microtubules within developing dendrites, thereby establishing their non-uniform microtubule polarity pattern. Here we used in situ hybridization to determine whether CHO1/MKLP1 is expressed in a variety of rodent neurons both in vivo and in vitro. These analyses revealed that CHO1/MKLP1 is expressed within various neuronal populations of the brain including those in the cerebral cortex, hippocampus, olfactory bulb and cerebellum. The messenger ribonucleic acid (mRNA) levels are high within these neurons well after the completion of their terminal mitotic division and throughout the development of their dendrites. After this, the levels decrease and are relatively low within the adult brain. Parallel analyses on developing hippocampal neurons in culture indicate that the levels of expression increase dramatically just prior to dendritic development, and then decrease somewhat after the dendrites have differentiated. Dorsal root ganglion neurons, which generate axons but not dendrites, express significantly lower levels of mRNA for CHO1/MKLP1 than hippocampal or sympathetic neurons. These results are consistent with the proposed role of CHO1/MKLP1 in establishing the dendritic microtubule array.

Animals↗
PubMed1999

Rat brain thioltransferase: regional distribution, immunological characterization, and localization by fluorescent in situ hybridization.

Thioltransferase (TTase) is a member of the family of thiol-disulfide oxidoreductases that are involved in the maintenance of sulfhydryl homeostasis in cells by catalyzing thiol-disulfide interchange reactions. One of the major consequences of oxidative stress in brain is the formation of protein-glutathione mixed disulfides (through oxidation of protein thiols), which can be reversed by TTase during the recovery of brain from oxidative stress. We therefore examined the presence of TTase in brain regions from rat. In the rat, TTase activity in the whole brain was comparable with the corresponding activity in liver, but significantly higher in hippocampus. The enzyme activity was significantly lower in striatum and cerebellum compared with activity in whole brain. Rat brain TTase shared immunological similarity with the human red blood cell enzyme, but not with the pig liver enzyme. The constitutive expression of the mRNA to TTase was demonstrable by northern blotting. Localization of the TTase mRNA in rat brain by fluorescent in situ hybridization showed the presence of high amounts of mRNA in the olfactory bulb, cortex, and hippocampus and its predominant localization in the neurons. TTase mRNA was also present in Purkinje cells in the cerebellum, in giant reticular neurons in the midbrain, and in the striatal and thalamic neurons. This study demonstrates the constitutive presence of a functional TTase system in brain and delineates the regional and cellular localization of the enzyme in rat brain.

Animals↗
PubMed2000

Differential expression of the G protein beta(5) gene: analysis of mouse brain, peripheral tissues, and cultured cell lines.

A neurally expressed heterotrimeric G protein beta subunit, Gbeta(5), has been found to exhibit functional specialization with respect to its interactions with effector targets and Galpha subunits. A splice variant of Gbeta(5) that contains an N-terminal 42-residue extension, Gbeta(5)-long, has been described in the retina. To define better the potential range of its specialized interactions, analysis of Gbeta(5) gene transcript and protein expression in mouse brain and other tissues and cell lines was performed. Quantification by ribonuclease protection assay of Gbeta(5) transcript expression in the developing brain demonstrates a fivefold increase that occurs postnatally. Analysis of transcript expression by in situ hybridization and ribonuclease protection assay indicates that the Gbeta(5) gene is differentially expressed among multiple adult mouse brain regions, including the motor and occipital cortex, the olfactory bulb and associated rhinencephalic structures, hypothalamus, pontine cochlear nuclei, and Purkinje cells in the cerebellum. Gbeta(5) is also expressed in several cultured cell lines of neuroendocrine origin, including murine alphaT3-1 pituitary gonadotrophs and GT1-7 hypothalamic cells, and rat PC12 pheochromocytoma cells. Immunoblotting of tissue homogenates with antibodies to two peptides common to Gbeta(5) and Gbeta(5)-long confirmed expression of Gbeta(5) in multiple brain regions and in spinal cord and expression of Gbeta(5)-long in retina. Taken together, these results suggest that the specialized molecular properties of Gbeta(5) have been adapted to diverse neural functions in the adult brain.

Aging↗
PubMed2005

A soluble mouse brain splice variant of type 2alpha corticotropin-releasing factor (CRF) receptor binds ligands and modulates their activity.

Peptides of the corticotropin-releasing factor (CRF) family signal through the activation of two receptors, CRF receptor type 1 (CRFR1) and type 2 (CRFR2), both of which exist as multiple splice variants. We have identified a cDNA from mouse brain encoding a splice variant, soluble CRFR2alpha (sCRFR2alpha), in which exon 6 is deleted from the gene encoding CRFR2alpha. Translation of this isoform produces a predicted 143-aa soluble protein. The translated protein includes a majority of the first extracellular domain of the CRFR2alpha followed by a unique 38-aa hydrophilic C terminus resulting from a frame shift produced by deletion of exon 6. By using RT-PCR and Southern hybridization, the relative mRNA expression levels of full-length (seven transmembrane domains) CRFR2alpha and the soluble form (sCRFR2alpha) in the mouse brain were measured with a single reaction. The results demonstrate high levels of expression of sCRFR2alpha in the olfactory bulb, cortex, and midbrain regions. A rabbit antiserum raised against a synthetic peptide fragment encoding the unique C terminus revealed specific sCRFR2alpha immunoreactivity in mouse brain slices by immunohistochemistry and in extracts of brain regions by RIA. Interestingly, the sCRFR2alpha immunoreactivity distribution closely approximated that of CRFR1 expression in rodent brain. A protein corresponding to sCRFR2alpha, expressed and purified from either mammalian or bacterial cell systems, binds several CRF family ligands with low nanomolar affinities. Furthermore, the purified sCRFR2alpha protein inhibits cellular responses to CRF and urocortin 1. These data support a potential role of the sCRFR2alpha protein as a possible biological modulator of CRF family ligands.

Alternative Splicing↗
PubMed2003

Pannexins, a family of gap junction proteins expressed in brain.

Database search has led to the identification of a family of proteins, the pannexins, which share some structural features with the gap junction forming proteins of invertebrates and vertebrates. The function of these proteins has remained unclear so far. To test the possibility that pannexins underlie electrical communication in the brain, we have investigated their tissue distribution and functional properties. Here, we show that two of these genes, pannexin 1 (Px1) and Px2, are abundantly expressed in the CNS. In many neuronal cell populations, including hippocampus, olfactory bulb, cortex and cerebellum, there is coexpression of both pannexins, whereas in other brain regions, e.g., white matter, only Px1-positive cells were found. On expression in Xenopus oocytes, Px1, but not Px2 forms functional hemichannels. Coinjection of both pannexin RNAs results in hemichannels with functional properties that are different from those formed by Px1 only. In paired oocytes, Px1, alone and in combination with Px2, induces the formation of intercellular channels. The functional characteristics of homomeric Px1 versus heteromeric Px1/Px2 channels and the different expression patterns of Px1 and Px2 in the brain indicate that pannexins form cell type-specific gap junctions with distinct properties that may subserve different functions.

Animals↗
PubMed1989

Brain phospholipase C isozymes: differential mRNA localizations by in situ hybridization.

mRNAs for isozymes of phospholipase C (PLC) were localized in rat brain by in situ hybridization with oligonucleotide probes for PLC isozymes I, II, and III of Rhee's group [Suh, P.-G., Ryu, S. H., Moon, K. H., Suh, H. W. & Rhee, S. G. (1988) Proc. Natl. Acad. Sci. USA 85, 5419-5423 and (1988) Cell 54, 161-169], and isozyme I of Bennett and Crooke [Bennett, C. F., Balcarek, J. M., Varrichio, A. & Crooke, S. T. (1988) Nature (London) 334, 268-270], which we designate PLC-A. The isozymes displayed different localizations. PLC-A mRNA was highest in the mitral cell layer of the olfactory bulb, choroid plexus, hippocampus and dentate gyrus, magnocellular hypothalamic nuclei, rostral raphe nuclei, and cerebellar Purkinje cells. PLC-I was highest in the internal granular cell layer of the olfactory bulb, cerebral cortex, caudate, nucleus of the lateral olfactory tract, reticular nucleus of thalamus, hippocampus and dentate gyrus, and granule cell layer of the cerebellum. PLC-II had a more widespread distribution, with relatively high levels in the internal granular layer of the olfactory bulb, hippocampus and dentate gyrus, and cerebellar Purkinje and granule cells. PLC-III label was low throughout the brain. These distributions suggest selective coupling of individual PLC isozymes with particular postsynaptic receptors. PLC-A may be preferentially associated with 5-hydroxytryptamine 1C receptors, vasopressin V1 receptors, and a subtype of glutamate receptors. PLC-I may be linked to muscarinic m1 and m3 receptors as well as other receptors. The distribution of PLC-II mRNA resembles that of src protooncogene, with which it displays sequence homology.

Animals↗
PubMed1999

Serotonin-2C receptor pre-mRNA editing in rat brain and in vitro by splice site variants of the interferon-inducible double-stranded RNA-specific adenosine deaminase ADAR1.

The interferon-inducible RNA-specific adenosine deaminase (ADAR1) is an RNA editing enzyme implicated in the site-selective deamination of adenosine to inosine in cellular pre-mRNAs. The pre-mRNA for the rat serotonin-2C receptor (5-HT2CR) possesses four editing sites (A, B, C, and D), which undergo A-to-I nucleotide conversions that alter the signaling function of the encoded G-protein-coupled receptor. Measurements of 5-HT2CR pre-mRNA editing in vitro revealed site-specific deamination catalyzed by ADAR1. Three splice site variants, ADAR1-a, -b, and -c, all efficiently edited the A site of 5-HT2CR pre-mRNA, but the D site did not serve as an efficient substrate for any of the ADAR1 variants. Mutational analysis of the three double-stranded (ds) RNA binding motifs present in ADAR1 revealed a different relative importance of the individual dsRNA binding motifs for deamination of the A site of 5-HT2CR and synthetic dsRNA substrates. Quantitative reverse transcription-polymerase chain reaction analyses demonstrated that the 5-HT2CR pre-mRNA was most highly expressed in the choroid plexus of rat brain. However, ADAR1 and the related deaminase ADAR2 showed significant expression in all regions of the brain examined, including cortex, hippocampus, olfactory bulb, and striatum, where the 5-HT2CR pre-mRNA was extensively edited.

Adenosine Deaminase↗
PubMed1999

Editing of glutamate receptor subunit B pre-mRNA by splice-site variants of interferon-inducible double-stranded RNA-specific adenosine deaminase ADAR1.

The interferon-inducible RNA-specific adenosine deaminase (ADAR1) is an RNA-editing enzyme that catalyzes the deamination of adenosine in double-stranded RNA structures. Three alternative splice-site variants of ADAR1 (ADAR1-a, -b, and -c) occur that possess functionally distinct double-stranded RNA-binding motifs as measured with synthetic double-stranded RNA substrates. The pre-mRNA transcript encoding the B subunit of glutamate receptor (GluR-B) has two functionally important editing sites (Q/R and R/G sites) that undergo selective A-to-I conversions. We have examined the ability of the three ADAR1 splice-site variants to catalyze the editing of GluR-B pre-mRNA at the Q/R and R/G sites as well as an intron hotspot (+60) of unknown function. Measurement of GluR-B pre-mRNA editing in vitro revealed different site-specific deamination catalyzed by the three ADAR1 variants. The ADAR1-a, -b, and -c splice variants all efficiently edited the R/G site and the intron +60 hotspot but exhibited little editing activity at the Q/R site. ADAR1-b and -c showed higher editing activity than ADAR1-a for the R/G site, whereas the intron +60 site was edited with comparable efficiency by all three ADAR1 splice variants. Mutational analysis revealed that the functional importance of each of the three RNA-binding motifs of ADAR1 varied with the specific target editing site in GluR-B RNA. Quantitative reverse transcription-polymerase chain reaction analyses of GluR-B RNA from dissected regions of rat brain showed significant expression and editing at the R/G site in all brain regions examined except the choroid plexus. The relative levels of the alternatively spliced flip and flop isoforms of GluR-B RNA varied among the choroid plexus, cortex, hippocampus, olfactory bulb, and striatum, but in all regions of rat brain the editing of the flip isoform was greater than that of the flop isoform.

Adenosine Deaminase↗