Genomic organization and alternative splicing of the human and mouse RPTPrho genes: Correction.
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Journal Article↗
Biomedical subjects
A Rotter
Publications and source records attributed to A Rotter.
Genomic organization and alternative splicing of the human and mouse RPTPrho genes.
BACKGROUND: Receptor protein tyrosine phosphatase rho (RPTPrho, gene symbol PTPRT) is a member of the type IIB RPTP family. These transmembrane molecules have been linked to signal transduction, cell adhesion and neurite extension. The extracellular segment contains MAM, Ig-like and fibronectin type III domains, and the intracellular segment contains two phosphatase domains. The human RPTPrho gene is located on chromosome 20q12-13.1, and the mouse gene is located on a syntenic region of chromosome 2. RPTPrho expression is restricted to the central nervous system. RESULTS: The cloning of the mouse cDNA, identification of alternatively spliced exons, detection of an 8 kb 3'-UTR, and the genomic organization of human and mouse RPTPrho genes are described. The two genes are comprised of at least 33 exons. Both RPTPrho genes span over 1 Mbp and are the largest RPTP genes characterized. Exons encoding the extracellular segment through the intracellular juxtamembrane 'wedge' region are widely spaced, with introns ranging from 9.7 to 303.7 kb. In contrast, exons encoding the two phosphatase domains are more tightly clustered, with 15 exons spanning approximately 60 kb, and introns ranging in size from 0.6 kb to 13.1 kb. Phase 0 introns predominate in the intracellular, and phase 1 in the extracellular segment. CONCLUSIONS: We report the first genomic characterization of a RPTP type IIB gene. Alternatively spliced variants may result in different RPTPrho isoforms. Our findings suggest that RPTPrho extracellular and intracellular segments originated as separate modular proteins that fused into a single transmembrane molecule during a later evolutionary period.
Journal Article↗
Chondroblastoma of the patella associated with an aneurysmal bone cyst.
Chondroblastoma is a rare, benign tumor of bone, accounting for about 1% of all bone tumor cases. It tends to affect the epiphyseal ends of long bones, most often in males during the first and second decades of life. It has well-characterized radiographic and histologic features but despite its histologically benign appearance a few cases of metastases have been reported. Local recurrences after curettage and bone grafting occur in 11% to 25% of cases. The features of a patellar chondroblastoma are the same as for other locations. In reviewing the literature we found an unusually high male-to-female ratio. It is interesting that the usual treatment of the patellar chondroblastoma has been patellectomy, whereas curettage and bone grafting has predominated in the other locations. We present a computer tomography and magnetic resonance imaging study of a case of chondroblastoma of the patella associated with an aneurysmal bone cyst. To our knowledge, it is the seventh case reported and the second with computer tomography and magnetic resonance imaging studies. We also review and discuss in detail all the cases of patellar chondroblastoma that we found in the literature.
Adult↗
Harmaline-induced changes in gamma aminobutyric acid(A) receptor subunit mRNA expression in murine olivocerebellar nuclei.
Increased CNS activity in the form of electrically or chemically induced seizures is known to alter the properties of GABA(A) receptors. The tremorgen, harmaline, causes a bursting pattern of activity in inferior olivary neurons, the effects of which are transmitted throughout the olivocerebellar circuit to other regions of the CNS. In situ hybridization was used to determine the effect of this increased activity on gamma aminobutyric acid(A) (GABA(A)) receptor subunit gene expression in the cerebellar Purkinje cell layer, deep cerebellar nuclei and inferior olivary complex of adult mice. In Purkinje cells, the expression of alpha(1), beta(2), and gamma(2) mRNAs was increased only slightly (<5%) by harmaline administration, while in deep cerebellar neurons, beta(2) transcript levels were initially elevated (26%), but dropped to control levels immediately thereafter. The expression of alpha(2), alpha(4), beta(3) and gamma(1) mRNAs in olivary neurons was affected differentially by harmaline administration. The alpha(4) transcript was increased, reaching >60% above control levels at 6 h post-injection. A smaller increase was observed for alpha(2) mRNA, while beta(3) and gamma(1) transcripts dropped below control levels during the same period. The expression of corticotropin-releasing factor mRNA was also elevated in the olivary complex. These data indicate that while Purkinje cells and deep cerebellar neurons are only minimally affected, harmaline induced changes in cellular properties may result in increased numbers of alpha(4)-containing, diazepam-insensitive, GABA(A) receptors in olivary neurons.
Animals↗
Cyclops syndrome occurring after partial rupture of the anterior cruciate ligament not treated by surgical reconstruction.
Cyclops syndrome is one of the specific causes of loss of extension of the knee following anterior cruciate ligament (ACL) reconstruction. The syndrome is manifested by progressive loss of extension associated with pain and audible clunk at terminal extension caused by a pedunculated nodule of fibrovascular proliferative tissue usually arising from the graft. The entity has been described recently and has been reported exclusively as a complication of ACL reconstructions. We report the case of a patient with symptoms and arthroscopic and histological findings compatible with cyclops syndrome that developed after a partial ACL rupture that was not treated by surgical reconstruction. A different etiology and classical histological and immunohistological microscopic analysis of the nodule presented in this report may further clarify the pathogenesis of the cyclops syndrome.
Adult↗
Modulation of GABA(A) receptor subunit mRNA levels in olivocerebellar neurons of purkinje cell degeneration and weaver mutant mice.
In olivocerebellar circuits, changes in the subunit composition of GABA(A) receptors occur at a time of extensive synaptic remodeling. In the deep cerebellar nuclei, GABA(A) receptor alpha1, beta2, and gamma2 subunit mRNA expression increases throughout neonatal development, whereas in the inferior olivary complex, the perinatal combination of alpha3, alpha5, beta3, and gamma2 mRNAs switches to the adult combination of alpha2, alpha4, beta3 and gamma1 during postnatal week 2. In situ hybridization was used to examine changes in subunit expression in the olivocerebellar nuclei of Purkinje cell degeneration and weaver mutant mice. In Purkinje cell degeneration, subunit transcripts decreased below control levels in olivary neurons; however, alpha1, beta2, and gamma2 transcript levels were slightly increased in the medial nucleus of the deep cerebellar nuclei. In weaver olivary neurons, although the switch from early- to late-onset subunit mRNAs occurred as in normal mice, transcript levels were differentially modulated by the mutation. Our studies indicate that major alterations in synaptic connectivity do not prevent developmentally programmed switches in GABA(A) receptor gene expression but can modulate the timing and level of transcript expression in afferent and efferent neurons.
Animals↗
Novel receptor protein tyrosine phosphatase (RPTPrho) and acidic fibroblast growth factor (FGF-1) transcripts delineate a rostrocaudal boundary in the granule cell layer of the murine cerebellar cortex.
We have identified a novel receptor-like protein tyrosine phosphatase (RPTPrho) transcript whose expression in the cerebellar cortex is restricted to the granule cell layer of lobules 1-6. Acidic fibroblast growth factor (FGF-1) mRNA follows a similar cerebellar expression pattern. Together, the two markers define a sharp boundary in lobule 6, slightly caudal to the primary fissure. Anterior and posterior compartments became discernible only during postnatal weeks two and six, for RPTPrho and FGF-1, respectively. A rostrocaudal boundary in lobule 6 of the murine cerebellar cortex has also been identified morphologically by the effects of the meander tail mutation. The position of the RPTPrho and FGF-1 boundary on the rostrocaudal axis of the cerebellar cortex was close to, but not coincident with, the caudal extent of the disorganized anterior lobe of meander tail and the rostral extent of Otx-2 expression. The restricted pattern of FGF-1 and RPTPrho implies that these molecules may have specific signaling roles in the tyrosine phosphorylation/dephosphorylation pathway in the anterior compartment of the adult cerebellar cortex.
Animals↗
Identification and characterization of RPTP rho, a novel RPTP mu/kappa-like receptor protein tyrosine phosphatase whose expression is restricted to the central nervous system.
We describe the cloning, chromosomal localization and characterization of RPTPrho, a new member of the RPTPmu/kappa phosphatase subfamily. Receptor tyrosine phosphatases in this subfamily are comprised of a MAM domain near the N-terminal, an immunoglobulin-like domain, four fibronectin type III repeats, a single transmembrane domain, and a large juxtamembrane segment followed by two intracellular phosphatase domains. An alternatively spliced mini-exon was identified in the extracellular segment of RPTPrho, between the fourth fibronectin type III repeat and the transmembrane domain. The RPTPrho gene was mapped to human chromosome 20 and mouse chromosome 2. Northern blot analysis demonstrated that RPTPrho expression was restricted to the central nervous system, and in situ hybridization studies showed that the RPTPrho transcript was distributed throughout the murine brain and spinal cord. Exceptionally high levels of the transcript were present in the cortex and olfactory bulbs during perinatal development, but were down-regulated during postnatal week two. The motifs found in the extracellular segment of type II receptor protein tyrosine phosphatases are commonly found in neural cell adhesion molecules, suggesting that RPTPrho may be involved in both signal transduction and cellular adhesion in the central nervous system.
Adult↗
The GABAA receptor alpha 6 subunit gene (Gabra6) is tightly linked to the alpha 1-gamma 2 subunit cluster on mouse chromosome 11.
We have established that the GABAA receptor alpha 6 (Gabra6) and alpha 1 (Gabra 1) subunit genes are tightly linked on mouse chromosome 11 by analysing the strain distribution patterns of RFLPs for the two genes and microsatellite markers flanking these genes in 26 BXD recombinant inbred strains. These results further demonstrate clustering of the GABAA receptor subunit genes on mouse chromosomes and the synteny for these clusters between the mouse and human genomes.
Animals↗
Embryonic and postnatal expression of four gamma-aminobutyric acid transporter mRNAs in the mouse brain and leptomeninges.
The distribution of gamma-aminobutyric acid (GABA) transporter mRNAs (mGATs) was studied in mouse brain during embryonic and postnatal development using in situ hybridization with radiolabeled oligonucleotide probes. Mouse GATs 1 and 4 were present in the ventricular and subventricular zones of the lateral ventricle from gestational day 13. During postnatal development, mGAT1 mRNA was distributed diffusely throughout the brain and spinal cord, with the highest expression present in the olfactory bulbs, hippocampus, and cerebellar cortex. The mGAT4 message was densely distributed throughout the central nervous system during postnatal week 1; however, the hybridization signal in the cerebral cortex and hippocampus decreased during postnatal weeks 2 and 3, and in adults, mGAT4 labeling was restricted largely to the olfactory bulbs, midbrain, deep cerebellar nuclei, medulla, and spinal cord. Mouse GAT2 mRNA was expressed only in proliferating and migrating cerebellar granule cells, whereas mGAT3 mRNA was absent from the brain and spinal cord throughout development. Each of the four mGATs was present to some degree in the leptomeninges. The expression of mGATs 2 and 3 was almost entirely restricted to the pia-arachnoid, whereas mGATs 1 and 4 were present only in specific regions of the membrane. Although mGATs 1 and 4 may subserve the classical purpose of terminating inhibitory GABAergic transmission through neuronal and glial uptake mechanisms, GABA transporters in the pia-arachnoid may help to regulate the amount of GABA available to proliferating and migrating neurons at the sub-pial surface during perinatal development.
Animals↗
Characterization of the 1B promoter of fibroblast growth factor 1 and its expression in the adult and developing mouse brain.
The present study elucidates the molecular structure of a murine fibroblast growth factor 1 (FGF-1) promoter and describes its distribution in the adult and developing mouse brain. A cDNA clone coding for FGF-1 was isolated from a mouse brain cDNA library. Nucleotide sequence analysis revealed that the clone contained, in addition to the protein coding region, an untranslated exon (FGF-1B) 34 base pairs upstream of the translation start codon ATG. The mouse cDNA clone corresponded to the sole FGF-1 transcript in the brain. An RNase protection assay was used to map the transcription start site of the 1B promoter. The sequences upstream from the major transcription initiation site lacked consensus TATA or CAAT boxes. In situ hybridization with cRNA probes specific for the 1B transcript showed the message to be restricted largely to sensory and motor nuclei in the brainstem, and to the ventral spinal cord and cerebellum. Although occasional brainstem nuclei were labeled at low levels by embryonic day 18, the majority of nuclei became detectable autoradiographically during postnatal weeks 1 and 2, and adult levels of grain density were reached during the 3rd and 4th postnatal weeks. FGF-1B mRNA was expressed in phylogenetically older brain regions, which are involved primarily in processing information from exteroceptive sensory mechanoreceptors and in motor control. The relatively late developmental expression suggests a role for FGF-1 in neuronal maturation, rather than in neurogenesis.
Aging↗
[Favorable effects of epsilon-aminocaproic acid on the children with nephrotic syndrome and Schonlein-Henoch syndrome treated with corticosteroids].
An effect of EACA given in the daily dose of 85-230 mg/kg for 1-1-days on the activity of certain plasma protease inhibitors in 7 children with steroid-sensitive and steroid-dependent nephrotic syndrome (age between 3.5 and 18 years), and in 6 children with Schönlein-Henoch syndrome (aged between 3.5 and 6 years). Additionally, an effect of EACA on clinical status, dynamics of improvement, proteinuria and/or erythrocyturia, and incidence of adverse reactions was studied. It was found that EACA significantly increased antithrombin III activity by approximately 68.8% proteinase alpha 1-inhibitor by 41.8% alpha 2-antiplasmin by 55% in patients with nephrotic syndrome, and increased an activity of protease alpha 1-inhibitor by 75% in patients with Schönlein-Henoch syndrome. EACA given together with corticosteroids enhanced their efficiency manifested--especially in children with Schönlein-Henoch syndrome--by a rapid diminishment of skin changes, proteinuria and erythrocyturia. A drop in blood pressure, loose stools, upper respiratory inflammation, and fever were most frequent adverse reactions. EACA given alone produced rapidly increasing edema in patients with hephrotic syndrome. It seems that EACA may be used as an adjuvant therapy in some cases of nephrotic and Schönlein-Henoch syndromse.
Adolescent↗
Developmental changes in the expression of gamma-aminobutyric acidA/benzodiazepine receptor subunit mRNAs in the murine inferior olivary complex.
The pharmacological and physiological properties of ligand-gated ion channels are dependent on their subunit composition; spontaneously occurring changes in subunit composition during neuronal development may result in dramatic functional differences between embryonic and adult forms of the receptor complex. In the present study, in situ hybridization with antisense cRNA probes was used to examine the subunit composition of the gamma-aminobutyric acidA/benzodiazepine (GABAA/BZ) receptor in the developing inferior olivary complex. This receptor is thought to be a pentameric chloride channel comprised of selected alpha, beta, gamma, delta, and rho subunits, the majority of which have several isoforms: alpha 1-6, beta 1-4, gamma 1-4, and rho 1,2. Among the 13 subunit variants present in the mammalian central nervous system, alpha 2-5, beta 3, and gamma 1,2 mRNAs are expressed at significant levels in the inferior olivary complex. Two clearly different temporal patterns of GABAA/BZ receptor subunit mRNA expression were observed: The expression of alpha 3, alpha 5, beta 3, and gamma 2 mRNAs was at a peak during embryonic and early postnatal development followed by rapid down-regulation thereafter. Conversely, alpha 2, alpha 4, and gamma 1 mRNA expression was very low or absent during early development, and a pronounced increase was observed at the end of postnatal week 1. These studies suggest that there are developmental changes in the subunit composition of the GABAA/BZ receptor in inferior olivary neurons. These changes in subunit expression, which occur during a period of major alterations in afferent and efferent synaptic connections, may subserve a change in the role of GABA from its function as a neurotrophic factor to that of an inhibitory neurotransmitter.
Animals↗
Light-microscopic distribution and parasagittal organisation of muscarinic receptors in rabbit cerebellar cortex.
Recent studies on the effects of intrafloccular injections of muscarinic agonists and antagonists on compensatory eye movements in rabbit, indicate that muscarinic receptors may play a modulatory role in the rabbit cerebellar circuitry. It was previously demonstrated by Neustadt et al. (1988), that muscarinic receptors in rabbit cerebellar cortex are distributed into alternating longitudinal zones of very high and very low receptor density. In the present study, the zonal and cellular distribution of muscarinic receptors in the rabbit cerebellar cortex is investigated in detail using in vitro ligand autoradiography with the non-selective high-affinity antagonist [3H]quinuclidinyl benzilate (QNB), and the M2-specific antagonist [3H]AF-DX384, and immunocytochemistry with a monoclonal antibody specific for the cloned m2 muscarinic receptor protein. [3H]QNB and [3H]AF-DX384 binding sites and m2-immunoreactivity had similar overall distributions: dense labeling occurred in the dendritic arbors of a subset of Purkinje cells that are organized into parasagittal bands. A high level of muscarinic receptor labeling was also observed in a thin substratum of the molecular layer immediately above the Purkinje cell layer of the vestibulo-cerebellar lobules, i.e. the nodulus, the ventral uvula and the flocculus. Labeling in this stratum was associated with densely packed fibres, which were putatively identified as parallel fibres. Also Golgi cells, which were localized in part in the molecular layer, and a subset of mossy fibre rosettes, primarily concentrated in lobule VI, were immunoreactive for the m2 receptor. The parasagittal band of labeled Purkinje cell dendrites were most prominent in the anterior lobe (lobules I-V), in crus 1 and 2, in the flocculus, the ventral paraflocculus and the rostral folium of the nodulus. In other lobules, only infrequent Purkinje cells contained muscarinic receptors. The parasagittal organisation of muscarinic receptors differed from that of zebrin I, a Purkinje cell-specific protein which is often used as a marker of parasagittal parcelation of the cerebellar cortex. In the anterior lobe, however, there was a partial correspondence between muscarinic receptor and zebrin I bands. In the flocculus the distribution of muscarinic-receptor-positive Purkinje cells was related to the distinct white matter compartments as revealed with acetylcholinesterase (AChE) histochemistry. Muscarinic receptor-containing Purkinje cells were located primarily in the floccular zone 1, which is implicated in the control of eye movements about a horizontal axis. In order to relate the distribution of muscarinic receptor labeling to that of cholinergic nerve terminals, [3H]QNB binding sites and sodium-dependent [3H]hemicholinium-3 binding were compared. Sodium-dependent [3H]hemicholinium-3 binding sites mainly occurred in the granule cell layer of the vestibulo-cerebellum, which corresponds well with the distribution of the acetylcholine synthesizing enzyme, choline acetyltransferase (ChAT). However, sodium-dependent [3H]hemicholinium binding complemented, rather than co-localized with, muscarinic receptors which were primarily distributed in the molecular layer of the lobules of the vestibulo-cerebellar lobules. Their functional significance is puzzling, since their distribution does not correspond to that of markers of cholinergic innervation.
Acetylcholinesterase↗
Differential expression of GABAA/benzodiazepine receptor subunit mRNAs and ligand binding sites in mouse cerebellar neurons following in vivo ethanol administration: an autoradiographic analysis.
The gamma-aminobutyric acidA (GABAA)/benzodiazepine (BZ) receptor is a pentamer composed of subunits belonging to several classes (alpha 1-6, beta 1-4, gamma 1-4, delta, and rho 1 and rho 2). In situ hybridization, radioligand autoradiography, and immunocytochemistry were used to examine GABAA/BZ receptor alpha 1, alpha 6, beta 2, beta 3, and gamma 2 subunit expression in murine Purkinje, granule, and deep cerebellar neurons after in vivo ethanol exposure. Chronic ethanol treatment resulted in decreased alpha 1 subunit mRNA expression in each cell type, whereas the expression of alpha 6 and gamma 2 subunit mRNA levels increased; no changes were observed in the expression of beta 2 and beta 3 subunit mRNA. GABA and BZ agonist binding and antibody staining paralleled the changes in mRNA levels. Acute ethanol injection resulted in increased expression of alpha 1 and beta 3 mRNAs, whereas levels of alpha 6, beta 2, and gamma 2 mRNAs remained stable. Our results indicate that, in cerebellar neurons, the expression of specific GABAA/BZ receptor subunit mRNAs, polypeptides, and binding sites is independently regulated by in vivo administration of alcohol. The observed changes were not restricted to any one cerebellar cell type, because subunit expression in Purkinje, granule, and deep cerebellar cells was similarly affected.
Animals↗
New contraindication to intravascular iodinated contrast material.
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Acidosis, Lactic↗
Uncoupling of GABAA/benzodiazepine receptor alpha 1, beta 2, and gamma 2 subunit mRNA expression in cerebellar Purkinje cells of staggerer mutant mice.
The mammalian GABAA/benzodiazepine (GABAA/BZ) receptor is comprised of several subunit isoforms: alpha 1-6, beta 1-13, gamma 1-3 and delta. In the present studies, the expression of alpha 1, beta 2, and gamma 2 subunit mRNAs was examined in cerebellar Purkinje cells and deep cerebellar neurons of staggerer mutant mice during postnatal development. In control animals, the three subunit mRNAs were present at high density in Purkinje cells which, in adult animals, form a monolayer at the interface of the granule cell and molecular layers. The number of Purkinje cells in the staggerer cerebellar cortex is reduced; the majority of those that remain are retained within the granule cell layer and are unable to receive normal afferent synapses from granule cells. The three subunit mRNAs were ex pressed at similar levels in both staggerer and control Purkinje cells until postnatal day 9. After this time, although the alpha 1 subunit mRNA was maintained at control levels in staggerer Purkinje cells, the expression of beta 2 and gamma 2 subunit mRNAs decreased, and was largely absent by postnatal day 20. The loss of beta 2 and gamma 2 mRNA expression in staggerer was specific to Purkinje cells, since all three mRNAs were present throughout postnatal development in other brain regions, including the deep cerebellar nuclei. The present studies indicate that in cerebellar Purkinje cells, the GABAA/BZ receptor alpha 1, and beta 2, and gamma 2, subunit mRNAs are regulated by distinct mechanisms which are differentially affected by the staggerer mutation.
Aging↗
GABAA/benzodiazepine receptor alpha 6 subunit mRNA in granule cells of the cerebellar cortex and cochlear nuclei: expression in developing and mutant mice.
The gamma aminobutyric acidA/benzodiazepine (GABAA/BZ) receptor is a multisubunit (alpha, beta, gamma, delta, and rho) ligand-gated chloride channel; there are several variants of the alpha, beta, and gamma subunits, each of which has been localized throughout the central nervous system. A large number of GABAA/BZ subunit variants are expressed within the cerebellar cortex. In previous studies from other laboratories, alpha 6 subunit mRNA has been reported to be present exclusively in cerebellar granule cells. The developmental expression of alpha 6 mRNA in cerebellar and cochlear granule cells is of interest because it has been suggested that each of these cell types is derived from a common precursor pool. The polymerase chain reaction was used to generate a cDNA fragment encoding a portion of the M3-M4 intracellular loop of the alpha 6 subunit of the GABAA/BZ receptor. A [35S] riboprobe, transcribed from this cDNA fragment, was used to examine the expression of the alpha 6 subunit mRNA by in situ hybridization in developing normal mice and in adult mutant mice with known deficits in synaptic circuitry. A strong hybridization signal was observed over the granule cell layers of both the cerebellum and cochlear nuclei in adult mice. The signal over the cochlear nuclei appeared after birth toward the end of postnatal week 1, coinciding with the appearance of labeling in the cerebellar cortex. The intensity of the hybridization signal in both regions increased rapidly until postnatal day 14, after which it increased more gradually, reaching adult levels during postnatal week 3.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗