Developmental neurobiology. A real gene for reeler.
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Animals↗
Biomedical subjects
A M Goffinet
Publications and source records attributed to A M Goffinet.
A YAC contig containing the reeler locus with preliminary characterization of candidate gene fragments.
The reeler mutation in the mouse maps to proximal chromosome 5 and defines a key gene involved in brain development and evolution. No gene product is known, and the locus is currently being characterized by positional cloning. YAC clones corresponding to the closest markers D5Mit61 and D5Mit72 have been isolated. Cloned extremities of the YAC inserts were used to construct a 1.1-Mb contig, a 700-kb fragment of which was shown to contain the reeler locus. The integrity of the contig was verified by physical mapping on genomic DNA. The classical allele of the reeler mutation was associated with a 150-kb deletion between D5Mit61 and D5Mit72, while no gross chromosomal anomaly was found in the Orleans allele. Candidate coding sequences were isolated to construct a preliminary transcriptional map of the reeler region. Cosmid clones mapping within the rl deletion revealed a large transcript of more than 11 kb, which was present in normal embryonic brain but barely detectable in homozygous rlOrl/rlOrl embryonic brain, suggesting strongly that it corresponds to the reeler transcript.
Animals↗
A high-resolution genetic map of mouse chromosome 5 encompassing the reeler (rl) locus.
Using interspecific crosses between BALB/c and Mus spretus (SEG) mice, the murine reeler (rl) gene was mapped to the proximal region of chromosome 5 between the hepatocyte growth factor gene (Hgf) and the D5Mit66 microsatellite. The following order was defined: (centromere)-Cchl2a/Hgf-D5Mit1-D5Nam1/D5-Nam2 -rl/D5Mit61-D5Mit72-Xmv45-Htr5a- Peplb-D5Nam3-D5Mit66. Estimated distances between reeler and the nearest flanking markers D5Nam1 and D5Mit72 are 1.5 and 1.0 cM, respectively (95% confidence level), suggesting that the region could be physically mapped using a manageable number of YAC clones.
Alleles↗
The human transient subpial granular layer: an optical, immunohistochemical, and ultrastructural analysis.
The cytological features, origin, migration, and fate of the subpial granular layer cells of the human embryonic cerebral cortex are studied with light and electron microscopy, Golgi impregnations, and immunocytochemical staining with the microtubule associated protein 2 and glial fibrillary acidic protein antibodies. Subpial granular layer (SGL) cells form a distinct neuronal population in the molecular layer, characterized by a small dark nucleus with abundant chromatin clumps and prominent nucleoli, and a lightly stained cytoplasm containing few organelles. Somata and processes of SGL cells are intensively stained with microtubule-associated protein 2 antibody but do not express glial fibrillary acidic protein antibody. These cells apparently originate from the olfactory germinative zone. They follow two major strands from the olfactory subventricular zone to the subpial region. Subsequently, they migrate tangentially at the subpial level to all cortical regions, as is observed on Golgi and ultrastructural preparations. They constitute a transient population that penetrates the deep molecular layer and subsequently disappear from it. Several cytological features of these cells suggest an inward migration with growth of a radial process toward the cortical plate and subsequent nuclear translocation. The fate and the role of this new phylogenetic neuronal population has yet to be determined although the abundance of degenerating SGL cells in the deep molecular layer suggests at least partial degeneration.
Cerebral Cortex↗
The reeler gene: a clue to brain development and evolution.
Reeler mutant mice are characterized by profuse anomalies of cell positioning in the telencephalic and cerebellar cortices as well as by distinct malformations in non-cortical structures such as the inferior olive, the facial nerve nucleus and other brainstem nuclei. Studies of the embryonic development of these structures reveal that the early cell patterns formed by reeler neurons is consistently affected, so that the reeler gene plays an important role in the development of nerve cell patterns. Comparative studies of cortical development in reptiles suggest further that the mammalian type of cortical architectonics has been acquired progressively during brain evolution, and reveal some similarities in early cortical organization between reeler and reptilian, particularly chelonian, embryos, most notably the presence of an inverted gradient of cortical histogenesis. These observations point to a possible role of the reeler gene in cortical evolution. Although the factors responsible for the formation of neural cell patterns are largely unknown, most data point to the importance of cell-cell interactions. Cell-interaction molecules have probably been acquired during brain evolution and the reeler gene could act by perturbing, directly or indirectly, such cell interactions. The characterization and thus the cloning of the reeler gene is therefore important for our understanding of brain development. Recent data on the fine chromosomal mapping of the mutation prior to its positional cloning are reported.
Animals↗
Localization of the reeler gene relative to flanking loci on mouse chromosome 5.
The location of the reeler (rl) locus in mice in the paracentromeric part of chromosome (Chr) 5, proximal to the T(5;12)31H translocation breakpoint, has been confirmed. Analysis of DNA from animals with different doses of the proximal part of Chr 5 and from congenic mice showed that the Pgy-1 locus is the closet marker to rl, whereas En-2 is located farther, distal to the T31H breakpoint. Together with recently published evidence (Martin et al. 1989), our data suggest the following order: Cen-rl/Pgy-1-T31H-En-2.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Estimation of genetic distances between "reeler" and nearby loci on mouse chromosome 5.
Genetic distances between reeler (gene symbol rl) and the adjacent loci Pgy-1, Sor, and En-2 on proximal chromosome 5 were estimated using a backcross panel between rlOrl/rlOrl BALB/c and C57 mice. Pgy-1 and Sor are located approximately 7 cM away from and centromeric to reeler, whereas En-2 is located distally, approximately 8 cM from reeler. Backcrosses between rlOrl/rlOrl BALB/c and mice with the T31H translocation showed that the breakpoint is located less than 2 cM from reeler. Together with previous work, these observations suggest the following gene order: Cen-Sor/Pgy-1-rl-T31H-En-2-other loci.
Animals↗
Cerebellar phenotype of two alleles of the 'reeler' mutation on similar backgrounds.
Using congenic strains, the two alleles ('Ed' and 'Orl') of the reeler mutation in mice have been compared on two genetic backgrounds (B6 and C). The phenotypic differences in cerebellar organization between the 4 homozygous reeler mutant strains appeared related to the genetic background rather than to allelic differences.
Alleles↗
Glucose utilization in human visual cortex is abnormally elevated in blindness of early onset but decreased in blindness of late onset.
Glucose utilization has been studied in the visual cortex of blind human subjects, by comparison with normal volunteers, using positron emission tomography. In 6 subjects who became blind early in life ('early blindness'), metabolism in visual cortex was elevated, comparable to that of normal subjects studied with the eyes open. By contrast, glucose utilization in visual areas of 6 human subjects who became blind after completion of visual development ('late blindness') was decreased, slightly lower than in normal volunteers studied with the eyes closed. This unexpected difference between early and late blind subjects might reflect the persistence, in early blindness, of supranumerary synapses which would escape the normal developmental decrease in synaptic density during infancy.
Adult↗
Brain glucose metabolism in postanoxic syndrome. Positron emission tomographic study.
Thirteen positron emission tomographic studies of cerebral glucose utilization were carried out in 12 patients with postanoxic syndrome due to cardiac arrest. Seven subjects were in a persistent vegetative state. The 5 other subjects were normally conscious, but disclosed focal neurological signs. When compared with normal values, mean cerebral glucose metabolism was drastically decreased (+/- 50%) in vegetative subjects, and to a lesser degree (+/- 25%) in conscious patients. The most consistent regional alterations were found in the parieto-occipital cortex (9 cases), the frontier between vertebral and carotid arterial territories, followed by the frontomesial junction (5 cases), the striatum (3 cases with dystonia), thalamus (2 cases), and visual cortex (2 cases with cortical blindness). These data suggest that brain anoxia can result in global brain hypometabolism, which appears related to the vigilance state, as well as in regional alterations preferentially located in arterial border zones.
Adult↗
Measurement of cerebral blood flow with a bolus of oxygen-15-labelled water: comparison of dynamic and integral methods.
A method is presented for the measurement of cerebral blood flow (CBF) with a bolus of water labelled with oxygen 15. The method, which has been evaluated in normal volunteers, is based on Kety's model, with two additional parameters to account for the difference in the time of tracer arrival in the radial and carotid arteries ("delay") and for dispersion of the tracer in the body and/or blood counting systems. It combines the advantages of: (i) dynamic data collection for estimation of delay and dispersion; (ii) robustness and linearity of CBF estimates with an integral method; and (iii) simplicity of continuous external monitoring of arterial blood radioactivity, particularly with repeated measurements. An optimized protocol is proposed for routine applications in neurological and neurophysiological studies.
Adult↗
In vitro pharmacological profile of 3-N-(2-fluoroethyl)spiperone.
The binding affinities of spiperone and 3-N-(2-fluoroethyl)spiperone (FESP) have been compared for several rodent brain receptor sites and for inhibition of monoamine release and uptake sites. FESP and spiperone have almost identical profiles, namely a high affinity for dopamine-D2 and serotonin-S2 receptors, a low affinity for alpha 1-adrenergic receptors, and negligible binding to other sites. These results suggest that available data on spiperone binding may be applied to the interpretation of PET data obtained with FESP.
Animals↗
Neuronal ceroid-lipofuscinosis: preferential metabolic alterations in thalamus and posterior association cortex demonstrated by PET.
Regional brain glucose utilisation was investigated with positron emission tomography (PET) and fluorodeoxyglucose (FDG) in four siblings with neuronal ceroid-lipofuscinosis. A consistent pattern was found, namely a decrease of glucose utilisation in all grey structures but more marked at the level of the thalamus and posterior association cortex. The severity of metabolic anomalies was correlated with the degree of clinical impairment and with disease duration; they were the most severe in the oldest patient, who was also the most affected clinically, intermediate in two others, and minimal in the subject with the shortest period of development of the disease. These observations suggest that PET is useful for the definition of anatomical targets of metabolic diseases and for the investigation of their pathophysiology.
Age Factors↗
Determinants of nerve cell patterns during development: a review.
The aim of the work reviewed is to define some of the mechanisms which are implicated in the control of neural cell pattern formation in the developing central nervous system. This question was examined by studies of brain embryonic development in normal and reeler mutant mice, which are characterized by profuse architectonic anomalies. The adult reeler phenotype is characterized by extreme abnormalities of cell positioning in the telencephalic and cerebellar cortices as well as by distinct architectonic anomalies in non-cortical structures such as the inferior olive, the facial nerve nucleus and other brainstem nuclei. Studies of the embryonic development of these structures reveal that neurons are generated at the normal time and migrate along normal pathways. Moreover, the processes of directional axonal growth, differentiation of class-specific features of neurons and glia, and synaptogenesis appear unaffected by the reeler mutation. In all instances, however, the early cell patterns formed by reeler neurons is consistently less regular than in normal embryos. These data indicate that brain architectonics does not exclusively result from the maturation of cells, neurites and connections, but is also contingent upon a specific stabilization of early neurons at the end of migration. One may infer that the presence of a normal allele at the reeler locus is necessary for this stabilization to occur normally, or that it is submitted to genetic control. Although the factor(s) responsible for the stable configuration of neural cell patterns are still unknown, several hypotheses can be considered. There is ample evidence against the role of diffusible factors, mesodermal components and afferent fiber systems. So far, most data point to the importance of cell-cell interactions which can be of three types: homophilic (neuronal-neuronal), heterophilic (neuronal-glial), or both. The cell-interaction mechanism could have been acquired during brain evolution of the mammalian lineage and the reeler gene could act by perturbing, directly or indirectly, these cell interactions. A better definition of the mechanisms responsible for the organization of nerve cell patterns is central to our understanding of brain development in normal as well as in pathological states. By following the example of recent successful research on invertebrate brain development, we believe that the genetic approach to this important question is a valuable one.
Alleles↗
Brain glucose utilization under high sensory activation: hypoactivation of prefrontal cortex.
Brain glucose metabolism was studied, using positron emission tomography and [F-18]-2-deoxy-2-fluoro-D-glucose, in 13 healthy young adult men, at rest and under conditions of high visual and auditory stimulation with minor motor involvement. Despite high individual variations, the mean cerebral metabolic rate for glucose was highly increased during stimulation. Furthermore, the regional pattern of cerebral glucose utilization showed consistent differences between resting and activated states. Several brain areas, including temporal, motor-premotor and parieto-occipital cortices, and striatum, thalamus, and cerebellum showed a level of activation statistically comparable to that of mean gray. Significant preferential activation was found only in the visual cortex. By contrast, prefrontal and mesial cortical areas were relatively hypoactivated by the task. Inasmuch as prefrontal cortex is known to receive visual associative afferents, these observations are tentatively interpreted in terms of the "parallel" mode of information processing, along specific routes according to the environmental state.
Adult↗
Brain leukotriene C4 binding sites are S-alkylglutathione binding sites.
Leukotriene C4 binding to mouse brain membranes was readily displaced by S-alkylglutathione derivatives, with the affinity of the test compound increasing as the alkyl chain length increases. S-decylglutathione was as potent as leukotriene C4. These data suggest that brain membrane leukotriene C4 binding sites are S-alkylglutathione binding sites, possibly microsomal glutathione transferase.
Alkylation↗
Positron tomography demonstrates frontal lobe hypometabolism in progressive supranuclear palsy.
A regional analysis of cerebral glucose metabolism was carried out in 9 patients with progressive supranuclear palsy by using positron emission tomography with fluorodeoxyglucose as the tracer. A consistent metabolic map of frontal hypometabolism was found in 7 patients. Brain metabolism was normal in 1 subject and diffusely decreased in another. In the 7 patients with selective hypofrontality, motor and premotor areas were severely hypometabolic, while heteromodal association cortex and paralimbic regions were comparatively less affected. Although this pattern of frontal alterations, probably due to disconnection, appeared consistent with the clinical features of the disease, it proved difficult to correlate the metabolic maps with neuropsychological disturbances.
Aged↗
Decreased glucose utilization in the striatum and frontal lobe in probable striatonigral degeneration.
Nine positron emission tomography studies of regional cerebral glucose metabolism were performed in 7 patients with probable striatonigral degeneration, a disorder characterized by parkinsonian features and absent or poor response to L-dopa. When compared with values obtained in normal volunteers, mean cerebral glucose metabolism was slightly reduced in subjects with striatonigral degeneration who, in addition, had a marked (20.5%, +/- 3 SD) relative hypometabolism in putaminal and caudate nuclei. Significant hypometabolism was also found in motor/premotor as well as in prefrontal cortex. In 2 subjects who were studied twice a deterioration of relative striatal metabolism paralleled clinical evolution. Magnetic resonance imaging disclosed the presence of abnormal iron deposits in the putamen in all cases but showed no cortical anomalies. These results suggest that positron emission tomography with [18F]fluorodeoxyglucose may provide an index of cell and processes degeneration in the striatum in striatonigral degeneration and is able to detect functional deficits in frontal cortex. The presence of striatal hypometabolism might be a predictor of a poor response to L-dopa.
Aged↗