Biomedical subjects

Gundela Meyer

Publications and source records attributed to Gundela Meyer.

14 recordsLinked to original sources

PubMed2007

Magnetic resonance imaging and histological studies of corpus callosal and hippocampal abnormalities linked to doublecortin deficiency.

Mutated doublecortin (DCX) gives rise to severe abnormalities in human cortical development. Adult Dcx knockout mice show no major neocortical defects but do have a disorganized hippocampus. We report here the developmental basis of these hippocampal abnormalities. A heterotopic band of neurons was identified starting at E17.5 in the CA3 region and progressing throughout the CA1 region by E18.5. At neonatal stages, the CA1 heterotopic band was reduced, but the CA3 band remained unchanged, continuing into adulthood. Thus, in mouse, migration of CA3 neurons is arrested during development, whereas CA1 cell migration is retarded. On the Sv129Pas background, magnetic resonance imaging (MRI) also suggested abnormal dorsal hippocampal morphology, displaced laterally and sometimes rostrally and associated with medial brain structure abnormalities. MRI and cryosectioning showed agenesis of the corpus callosum in Dcx knockout mice on this background and an intermediate, partial agenesis in heterozygote mice. Wild-type littermates showed no callosal abnormalities. Hippocampal and corpus callosal abnormalities were also characterized in DCX-mutated human patients. Severe hippocampal hypoplasia was identified along with variable corpus callosal defects ranging from total agenesis to an abnormally thick or thin callosum. Our data in the mouse, identifying roles for Dcx in hippocampal and corpus callosal development, might suggest intrinsic roles for human DCX in the development of these structures.

Aborted Fetus↗

PubMed2007

Genetic control of neuronal migrations in human cortical development.

The early steps in corticogenesis are decisive for the correct unfolding of neurogenesis, neuronal migration and differentiation under tight genetic control. In this monograph, we outline the main events in human preplate formation, the gradual transformation of the preplate into the cortical plate, and the establishment of the transient compartments of the foetal cortical wall. The main neuronal populations of the embryonic and fetal cortex are presented according to their timetable of appearance and the expression of developmentally relevant gene products, with the main focus on members of the Reelin-Dab1 signalling pathway, LIS1 and Doublecortin, all of which are crucial for cortical migration. The often significant developmental differences between the lissencephalic rodent brain, which has become the prevailing model of corticogenesis, and the highly differentiated, gyrated human brain are pointed out and discussed.

Cell Differentiation↗

PubMed2006

Comparative aspects of p73 and Reelin expression in Cajal-Retzius cells and the cortical hem in lizard, mouse and human.

Cajal-Retzius (CR) cells of the mammalian neocortex co-express the extracellular matrix protein Reelin and p73, a transcription factor involved in cell death and survival. Most neocortical CR cells derive from the cortical hem, with minor additional sources. We analyzed the distribution of Reelin and p73 immunoreactive (ir) neurons in the telencephalon of Lacerta galloti from early embryonic stages to hatching. Numerous Reelin-ir cells appeared in the pallial MZ from the preplate stage onward. Conversely, p73-ir cells were rare in the pallial preplate and not observed in the cortical plate. Subpallial p73-ir cells spread from the septum and the telencephalic-diencephalic boundary to the pial surface of the basal forebrain and amygdala, respectively, where they co-expressed Reelin and p73. A small group of Reelin/p73-ir CR cells appeared in a rudimentary cortical hem at the interface of the medial cortex and choroid plexus. Comparison with early embryonic stages of mice and humans showed similar foci of p73-ir cells in the septum and at the telencephalic-diencephalic boundary and revealed an increasing prominence of the cortical hem, in parallel with increasing numbers of neocortical Reelin/p73 positive CR cells, which attain highest differentiation in the human brain. Our data show that Reelin-expression in the pallium is evolutionarily conserved and independent of a cortical hem, and suggest that p73 in the cortical hem may be involved in the evolutionary increase in number and complexity of the mammalian neocortical CR cells.

Animals↗

PubMed2006

Comparative aspects of cerebral cortical development.

This review aims to provide examples of how both comparative and genetic analyses contribute to our understanding of the rules for cortical development and evolution. Genetic studies have helped us to realize the evolutionary rules of telencephalic organization in vertebrates. The control of the establishment of conserved telencephalic subdivisions and the formation of boundaries between these subdivisions has been examined and the very specific alterations at the striatocortical junction have been revealed. Comparative studies and genetic analyses both demonstrate the differential origin and migratory pattern of the two basic neuron types of the cerebral cortex. GABAergic interneurons are mostly generated in the subpallium and a common mechanism governs their migration to the dorsal cortex in both mammals and sauropsids. The pyramidal neurons are generated within the cortical germinal zone and migrate radially, the earliest generated cell layers comprising preplate cells. Reelin-positive Cajal-Retzius cells are a general feature of all vertebrates studied so far; however, there is a considerable amplification of the Reelin signalling with cortical complexity, which might have contributed to the establishment of the basic mammalian pattern of cortical development. Based on numerous recent observations we shall present the argument that specialization of the mitotic compartments may constitute a major drive behind the evolution of the mammalian cortex. Comparative developmental studies have revealed distinct features in the early compartments of the developing macaque brain, drawing our attention to the limitations of some of the current model systems for understanding human developmental abnormalities of the cortex. Comparative and genetic aspects of cortical development both reveal the workings of evolution.

Animals↗

PubMed2006

Human disorders of cortical development: from past to present.

Epilepsy and mental retardation, originally of unknown cause, are now known to result from many defects including cortical malformations, neuronal circuitry disorders and perturbations of neuronal communication and synapse function. Genetic approaches in combination with MRI and related imaging techniques continually allow a re-evaluation and better classification of these disorders. Here we review our current understanding of some of the primary defects involved, with insight from recent molecular biology advances, the study of mouse models and the results of neuropathology analyses. Through these studies the molecular determinants involved in the control of neuron number, neuronal migration, generation of cortical laminations and convolutions, integrity of the basement membrane at the pial surface, and the establishment of neuronal circuitry are being elucidated. We have attempted to integrate these results with the available data concerning, in particular, human brain development, and to emphasize the limitations in some cases of extrapolating from rodent models. Taking such species differences into account is clearly critical for understanding the pathophysiological mechanisms associated with these disorders.

Animals↗

PubMed2006

Multiple isoforms of the tumor protein p73 are expressed in the adult human telencephalon and choroid plexus and present in the cerebrospinal fluid.

p73, a homolog of the p53 tumor suppressor, codes for full-length transactivating (TA) and N-terminally truncated (DeltaN) isoforms, with pro- and anti-apoptotic activities, respectively. We examined the expression of the main p73 isoforms in adult human and mouse telencephalon and choroid plexus by immunohistochemistry on paraffin sections, and immunoblotting (IB) of tissue extracts and cerebrospinal fluid (CSF), using antibodies against different protein domains. Cortical neurons expressed TAp73 predominantly in the cytoplasm and DeltaNp73 mainly in the nucleus, with partial overlap in the cytoplasm. Highest expression was found in the hippocampus. IB showed an array of TAp73 variants in adult human cortex and hippocampus. IB of human choroid plexus and CSF using TAp73-specific antibodies revealed the presence of a approximately 90-kDa protein whose molecular weight was reduced after N-deglycosylation, suggesting that glycosylated TAp73 is exported into the CSF. In the mouse, high expression of TAp73 was also detected in the subcommissural organ (SCO), an ependymal gland absent in adult humans. TAp73 colocalized with anti-fibra-Reissner-antibody (AFRU), which is a marker of Reissner's fiber, the secreted SCO product. p73-deficient mice had generalized cortical hypoplasia and hydrocephalus; in addition, we observed a dramatic size reduction of the choroid plexus. However, the SCOs were apparently unaltered and continued to secrete Reissner's fiber. Our findings point to complex and widespread p73 activities in the maintenance of adult cortical neurons and in brain homeostasis. TAp73 in the CSF may play important roles in the maintenance of the adult ventricular wall as well as in the development of the proliferating neuroepithelium.

Adolescent↗

PubMed2004

A maternal blood-borne factor promotes survival of the developing thalamus.

In this report, we describe the identification of a polypeptide survival-promoting factor that is produced by maternal and early postnatal peripheral blood mononuclear cells (PBMCs) of the immune system in Long-Evans rats and humans. The factor, termed Y-P30, most likely arises from proteolytic processing of a larger precursor protein and accumulates mainly in pyramidal neurons of the developing cortex and hippocampus but not in astrocytes. It was released from neurons grown in culture and substantially promotes survival of cells in explant monocultures of perinatal thalamus from the offspring. Y-P30 mRNA was not detectable in infant or adult brain and was present only in blood cells of pregnant rats and humans but not in nonpregnant controls. However, Y-P30 transcription could be induced in PBMCs of adult animals by a central nervous system lesion (i.e., optic nerve crush), which points to a potential role of the factor not only in neuronal development but also in neuroinflammation after white matter injury.

Animals↗

PubMed2004

Developmental roles of p73 in Cajal-Retzius cells and cortical patterning.

To examine the role of the p53 homolog p73 in brain development, we studied p73-/-, p73+/-, E2F1-/-, and reeler mutant mice. p73 in developing brain is expressed in Cajal-Retzius (CR) cells, the cortical hem, and the choroid plexus. p73-expressing CR cells are lost in p73-/- embryos, although Reelin is faintly expressed in the marginal zone. Ectopic neurons in the p73-/- preplate and cortical hem at embryonic day 12 implicate p73 in the early developmental program of the cortex; however, preplate partition and early cortical plate formation are not disturbed. Postnatal p73-/- mice show a mild hypoplasia of the rostral cortex and a severely disrupted architecture of the posterior telencephalon. In the developing p73-/- hippocampus, the most striking abnormality is the absence of the hippocampal fissure, suggesting a role of p73 in cortical folding. p73+/- mice have a less severe cortical phenotype; they display a dorsal shift of the entorhinal cortex and a reduced size of occipital and posterior temporal areas, which acquire entorhinal-like features such as Reelin-positive cells in layer II. CR cells appear unaffected by heterozygosity. We relate the malformations of the posterior pole in p73 mutant mice to alterations of p73 expression in the cortical hem and suggest that p73 forms part of an early signaling network that controls neocortical and archicortical regionalization. In mice deficient for the transcription factor E2F1, a main activator of the TAp73 (transactivating p73) isoform, we find a defect of the caudal cortical architecture resembling the p73+/- phenotype along with reduced TAp73 protein levels and propose that an E2F1-TAp73 dependent pathway is involved in cortical patterning.

Animals↗

PubMed2004

p73 and Reelin in Cajal-Retzius cells of the developing human hippocampal formation.

In the fetal human hippocampus, Cajal-Retzius (CR) cells coexpress p73, a p53-family member involved in cell survival and apoptosis, and the glycoprotein reelin, crucial for radial migration. We distinguish two populations of putative CR cells. (1). p73/reelin expressing cells appear around 10 gestational weeks (GW) at the cortico-choroid border in the temporal horn of the lateral ventricle (the ventral cortical hem) and occupy the marginal zone (MZ) overlying the ammonic and dentate primordia. (2). Additional p73-positive cells appear from 14 GW onward in the neuroepithelium near the dentate-fimbrial boundary and spread toward the pial surface, flanking the migrating secondary dentate matrix. From 13 to 17 GW, large parts of the dentate gyrus are almost devoid of CR cells. p73/Reelin-positive CR cells appear in the MZ of the suprapyramidal blade at 16 GW and around 21 GW in the infrapyramidal blade. The p73-positive cells of the dentate-fimbrial boundary express reelin when they are close to the pial surface, suggesting that they differentiate into CR cells of the infrapyramidal blade. Reelin-positive, p73-negative interneurons are prominent in the prospective strata lacunosum-moleculare and radiatum of cornu ammonis as early as 14 GW; in the dentate molecular layer and hilus they appear around midgestation. We propose that CR cells of the human hippocampal formation belong to two distinct cell populations: an early one derived from the ventral cortical hem and mainly related to migration of the ammonic and dentate plates and a later appearing one derived from the dentate-fimbrial neuroepithelium, which may be related to the protracted neurogenesis and migration of dentate granule cells, particularly of the infrapyramidal blade.

Cell Adhesion Molecules, Neuronal↗

PubMed2003

Reelin-expressing neurons in the postnatal and adult human hippocampal formation.

Reelin plays a major role in the development of laminated brain structures. In the developing neocortex and hippocampus, Reelin is secreted by Cajal-Retzius cells in the marginal zone. In the present report, we characterize Reelin-immunoreactive neurons in the perinatal and adult human hippocampal formation. Two main populations of cells are described: Cajal-Retzius cells and interneurons. Cajal-Retzius cells are defined as neurons that coexpress Reelin and p73, a nuclear protein of the p53 family. Colocalization experiments of p73 with calcium-binding proteins indicate that most Cajal-Retzius cells express calretinin, but not calbindin. Cajal-Retzius cell density decreases dramatically during the postnatal period, although a few Reelin/p73-positive neurons are still found in the adult. At birth, Reelin-positive, p73-negative neurons are present in all layers of the hippocampal formation. Their morphology and localization indicate that they belong to a heterogeneous population of interneurons. They are numerous in the strata lacunosum-moleculare and radiatum of CA1-CA3, in the hilus, and in the molecular layer of the dentate gyrus, but less common in stratum oriens and alveus, and rare in the principal cell layers. Subpopulations of Reelin-positive interneurons express calretinin or calbindin. The packing density of Reelin-positive cells decreases postnatally, which may be related to the disappearance of Cajal-Retzius cells and to the growth of the hippocampal formation. The presence of Reelin-immunoreactive cells in the adult hippocampal formation indicates that Reelin is not restricted to development but that it may have additional functions in adult life.

Adolescent↗

PubMed2003

Disabled-1 mRNA and protein expression in developing human cortex.

Disabled-1 (Dab1) forms part of the Reelin-Dab1 signalling pathway that controls neuronal positioning during brain development; Dab1 deficiency gives rise to a reeler-like inversion of cortical layers. To establish a timetable of Dab1 expression in developing human brain, Dab1 mRNA and protein expression were studied in prenatal human cortex. The earliest Dab1 signal was detected at 7 gestational weeks (GW), the stage of transition from preplate to cortical plate, suggesting a role of the Reelin-Dab1 signalling pathway in preplate partition. From 12 to 20 GW, the period of maximum cortical migration, Dab1 expression was prominent in the upper tiers of the cortical plate, to decline after midgestation. Radially orientated apical dendrites of Dab1-expressing neurons indicated a predominant pyramidal phenotype. Pyramidal cells in hippocampus and entorhinal cortex displayed a more protracted time of Dab1 expression compared to neocortex. In addition, at later stages (18-25 GW), Dab1 was also expressed in large neurons scattered throughout intermediate zone and subplate. From 14 to 22 GW, particularly high levels of Dab1 mRNA and protein were observed in cells of the ventricular/subventricular zone displaying the morphology of radial glia. The partial colocalization of vimentin and Dab1 in cells of the ventricular zone supported a radial glia phenotype. The concentration of Dab1 protein in ventricular endfeet and initial portions of radial processes of ventricular-zone cells points to a possible involvement of Dab1 in neurogenesis. Furthermore, a subset of Cajal-Retzius cells in the marginal zone colocalized Dab1 and Reelin, and may thus represent a novel target of the Reelin-Dab1 signalling pathway.

Adaptor Proteins, Signal Transducing↗

PubMed2003

Combining theoretical and experimental approaches to understand the circadian clock.

This review is intended as a summary of our work carried out as part of the German Research Association (DFG) Center Program on Circadian Rhythms. Over the last six years, our approach to understanding circadian systems combined theoretical and experimental tools, and Gonyaulax and Neurospora have proven ideal for these efforts. Both of these model organisms demonstrate that even simple circadian systems can have multiple light input pathways and more than one rhythm generator. They have both been used to elaborate basic circadian features in conjunction with formal models. The models introduce the "zeitnehmer," i.e., a clock-regulated input pathway, to the conceptual framework of circadian systems, and proposes networks of individual feedbacks as the basis for circadian rhythmicity.

Animals↗

PubMed2002

Expression of p73 and Reelin in the developing human cortex.

Cajal-Retzius (CR) cells of the developing neocortex secrete Reelin (Reln), a glycoprotein involved in neuronal migration. CR cells selectively express p73, a p53 family member implicated in cell survival and apoptosis. Immunocytochemistry in prenatal human telencephalon reveals a complex sequence of migration waves of p73- and Reln-immunoreactive (IR) neurons into the cortical marginal zone (MZ). At early preplate stages, p73/Reln-IR cells arise in distinct sectors of the telencephalon, including cortical primordium and ganglionic eminences. After the appearance of the cortical plate, further p73/Reln-IR cells originate in the medial periolfactory forebrain. In addition, p73 marks a novel cell population that appears at the choroid-cortical junction or cortical hem before the emergence of the dorsal hippocampus. A pronounced mediolateral gradient in the density of p73/Reln-IR neurons in the neocortical MZ at 8 gestational weeks suggests that a subset of CR cells migrate tangentially from cortical hem and taenia tecta into neocortical territory. This hypothesis is supported by the absence of p73-transcripts in prospective neocortex of p73-/-mice at embryonic day 12 (E12), whereas they are present in cortical hem and taenia tecta. In the p73-/- preplate, Reln is faintly expressed in a calretinin-positive cell population, not present in this form in the E12 wild-type cortex. At P2, Reln-IR CR cells are undetectable in the p73-/- cortex, whereas Reln-expression in interneurons is unchanged. Our results point to a close association between p73 and Reln in CR cells of the developing neocortex, with a partial dissociation in early preplate and basal telencephalon, and to a p73-mediated role of the cortical hem in neocortical development.

Animals↗

PubMed2002

Selective expression of doublecortin and LIS1 in developing human cortex suggests unique modes of neuronal movement.

The genes doublecortin (DCX) and LIS1 are required for proper cortical neuronal migration and differentiation in humans. Here, we study the expression pattern of the encoded proteins of these genes in developing human brain. LIS1 stained virtually all migrating neurons throughout periods of development. Initially, DCX extensively overlapped with Reelin in early preplate stage in radially oriented columns of cells in the ventricular zone, whereas at later stages, the majority of DCX-positive cells were horizontally oriented. During the cortical plate stage, two opposite patterns of DCX expression were found: in radially oriented apical processes, presumably of pyramidal cells in the cortical plate, and in non-radially oriented mono- or bipolar neurons with migratory morphologies in the deep compartments of the cerebral wall. The extensive co-localization of DCX and Calretinin in non-radially oriented neurons suggested a non-pyramidal phenotype. These cells assumed a more vertical orientation upon entering the subplate. In addition, DCX was expressed by cells in the subpial granular layer and by Cajal-Retzius cells. In a 19 week human fetal cortex with a LIS1 mutation, the number of Reelin-expressing Cajal-Retzius cells was reduced and their morphology was abnormal. DCX was expressed by cells in all regions, but in extremely low numbers, suggesting that LIS1 deficiency adversely affects the migration and differentiation of DCX- and Reelin-positive neurons.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗