bioRxiv (Cold Spring Harbor Laboratory), May 17, 2024
We acknowledge the Regionalverband Ruhr, Essen, Germany, for the interest in our work. We thank A... more We acknowledge the Regionalverband Ruhr, Essen, Germany, for the interest in our work. We thank Andrea Räk and Christian Riedel for technical support. We thank Prof. Schmelz and Prof. Engelhardt, University Mannheim, Germany, for donating the P5 piglet brain.
Knowledge on cortical development is based mainly on small rodents besides primates and carnivore... more Knowledge on cortical development is based mainly on small rodents besides primates and carnivores, all being altricial nestlings. Ungulates are precocial and born with nearly mature sensory and motor systems. Almost no information is available on ungulate brain development. Here, we analyzed European wild boar cortex development, focusing on the neuropeptide Y immunoreactive (NPY-ir) neuron system in dorsoparietal cortex from E35 to P30. Transient NPY-ir neuron types including archaic cells of the cortical plate and axonal loop cells of the subplate which appear by E60 concurrent with the establishment of the ungulate brain basic sulcal pattern. From E70, NPY-ir axons have an axon initial segment which elongates and shifts closer towards the axon's point of origin until P30. From E85 onwards (birth at E114), NPY-ir neurons in cortical layers form basket cell-like local and Martinotti cell-like ascending axonal projections. The mature NPY-ir pattern is recognizable at E110. Together, morphologies are conserved across species, but timing is not: in pig, the adult pattern largely forms prenatally.
A karyometric study of the medial and the lateral preoptic area of the male albino mouse has been... more A karyometric study of the medial and the lateral preoptic area of the male albino mouse has been carried out with the aid of a Leitz Image Analysis System (ASM). We have measured nuclear sizes of a control group of sixty mice, aged from the 5th to the 190th day of life. Another group of prepuberally castrated male mice, has been studied at the 25th, 35th, 45th, 55th and 85th postnatal day. The medial and the lateral preoptic area show different development patterns in the control group, and differential effects of castration in these zones were observed. The medial preoptic area, which has frequently been related to changes of sex hormone levels, experiments more important and statistically significant variations than the lateral preoptic area.
A karyometric study of the c~pendymal cells of the subcommissural organ (SCO) was made in male al... more A karyometric study of the c~pendymal cells of the subcommissural organ (SCO) was made in male albino mice castrated at 20 days and examined at 25, 35, 45, 55 and g5 days of life, and in control group.~ of the respective ages. The values of the nuclear areas and perimeters of SCO cells as well as those of the global volume of the SCO are significantly lower in the experimental groups, and the nuclear membrane shows less invaginations. No changes are observed after gonadectomy in the subjacent thalamic ependyma.
This review aims to provide examples of how both comparative and genetic analyses contribute to o... more 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-po...
Epilepsy and mental retardation, originally of unknown cause, are now known to result from many d... more 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...
The canonical view of neuronal function is that inputs are received by dendrites and somata, beco... more The canonical view of neuronal function is that inputs are received by dendrites and somata, become integrated in the somatodendritic compartment and upon reaching a sufficient threshold, generate axonal output with axons emerging from the cell body. The latter is not necessarily the case. Instead, axons may originate from dendrites. The terms “axon carrying dendrite” (AcD) and “AcD neurons” have been coined to describe this feature. Here, we report on the diversity of axon origins in neocortical pyramidal cells. We found that in non-primates (rodent, cat, ferret, pig), 10-21% of pyramidal cells of layers II-VI had an AcD. In marked contrast, in macaque and human, this proportion was lower, and it was particularly low for supragranular neurons. Unexpectedly, pyramidal cells in the white matter of postnatal cat and aged human cortex exhibit AcDs to much higher percentages. In rodent hippocampus, AcD cells are functionally ‘privileged’, since inputs here can circumvent somatic integra...
The human insula is a key node in a neuronal network which integrates interoceptive stimuli from ... more The human insula is a key node in a neuronal network which integrates interoceptive stimuli from the own body, and exteroceptive stimuli from the environment, and thus maintains the autonomic, emotional and socio-cognitive homeostasis of the body. In the last years, the insula has come into the focus of attention. Comparative anatomical studies showed that in many species the insula forms the lateral edge of the cortex. Very little is known about the prenatal development of the human insula, which is the first cortical region to mature. The origin of the pyramidal neurons for the insula is a small sector of the proliferating ventricular/subventricular zone at the cortico-striatal boundary (CSB). The CSB contains the radial glia cells, which are stem cells and give rise to a dense fascicle of radial glia processes. This fascicle traverses the external capsule and serves as a migration substrate for the neuroblasts on their way from the CSB into the insula. Around the 10/11th week of ...
Proceedings of the National Academy of Sciences, 1998
Behavioral and neurophysiological studies suggest that skill learning can be mediated by discrete... more Behavioral and neurophysiological studies suggest that skill learning can be mediated by discrete, experience-driven changes within specific neural representations subserving the performance of the trained task. We have shown that a few minutes of daily practice on a sequential finger opposition task induced large, incremental performance gains over a few weeks of training. These gains did not generalize to the contralateral hand nor to a matched sequence of identical component movements, suggesting that a lateralized representation of the learned sequence of movements evolved through practice. This interpretation was supported by functional MRI data showing that a more extensive representation of the trained sequence emerged in primary motor cortex after 3 weeks of training. The imaging data, however, also indicated important changes occurring in primary motor cortex during the initial scanning sessions, which we proposed may reflect the setting up of a task-specific motor processi...
CeLL CyCLe news & views 1186 Cell Cycle volume 10 issue 8 Mucous epithelia and their glands show ... more CeLL CyCLe news & views 1186 Cell Cycle volume 10 issue 8 Mucous epithelia and their glands show continuous self-renewal, from multipotent somatic (adult) stem cells as well as from a pool of transit-amplifying cells that gradually differentiate and migrate to their final destinations. The mammalian stomach, along with the intestine, is one of the organs with the highest cellular turnover. The gastric regeneration dynamics were established in detail in the mouse by Leblond and his coworkers about 20 years ago. 1 The morphology and the self-renewal of the human stomach differ in important details from the murine sytem. 2 Histologically, the human gastric mucosa, which is of endodermal origin, is divided into three zones: the cardiac zone, the fundus/
Cajal-Retzius (CR) cells are the most significant source of reelin, an extracellular matrix glyco... more Cajal-Retzius (CR) cells are the most significant source of reelin, an extracellular matrix glycoprotein essential for cortical development. Strategically located in the marginal zone, CR cells control radial migration and laminar positioning of pyramidal neurons of the cortical plate. They degenerate and undergo cell death when cortical migration is completed. In human cortex development, reelin-expressing CR cells are already present in the early preplate, and continue to increase in number after the appearance of the cortical plate. In the course of the first half of gestation, the reelin signal in the marginal zone undergoes a huge amplification in parallel with the growth of the cortical plate and the expansion of the cortical surface. A significant source of CR cells is the cortical hem, a putative signalling centre at the interface of the prospective hippocampus and the choroid plexus. Hem-derived CR cells co-express reelin and p73, a transcription factor of the p53-family. They form the predominant CR cell population of the human neocortex. Characteristically, CR cells express the anti-apoptotic isoform DeltaNp73 which may be responsible for the protracted lifespan of human CR cells and the morphological differentiation of their axonal plexus. This dense fibre plexus, absent in lower mammals, amplifies the reelin-signal and establishes a physical boundary between the cortical plate and the marginal zone. In this review, we analyze the multiple sources of reelin ⁄ p73 positive CR cells at the interface of various telencephalic centres and the choroid plexus of the lateral ventricles. Additional populations of CR cells may derive from the thalamic eminence in the ventral thalamus and from the strionuclear neuroepithelium, or 'amygdalar hem'. Comparative studies in a variety of species indicate that the cortical hem is the main origin of CR cells destined for the neocortex, and is most highly developed in the human brain. The close association between cortical hem and choroid plexus suggests a concerted role in the evolutionary increase of CR cells, amplification of the reelin signal in the marginal zone, and cortical expansion.
of the gyri, where radial fi ber fascicles intermingle with radial rows of layer VIb neurons and ... more of the gyri, where radial fi ber fascicles intermingle with radial rows of layer VIb neurons and IN seem to be continuous with neurons of layer VIb. 3. The highest density of IN is in the WM immediately subjacent to the gray matter, in the zone that contains the association or "U" fi bers of the cortical convolutions, and then gradually decreases with increasing distance from the gray matter. Very few neurons lie among the long fi ber tracts in the deep WM, such as internal capsule, superior and inferior longitudinal fasciculi, or corpus callosum. However, there is no sharp boundary between the superfi cial WM, rich in IN, and the deep WM, where IN are sparse. There may also be regional differences in the density of IN, with lowest numbers in the visual cortex, and higher numbers in the frontal and prefrontal cortex. 4. The IN display a variety of morphologies ranging from pyramidal-like to bipolar and multipolar. They can be classifi ed into the two main neuronal categories also present in the gray matter, namely excitatory glutamatergic cells and inhibitory GABAergic neurons. 5. IN of the cortical WM are often referred to as "subplate" cells. During development, the subplate is a transient cell compartment just below the future layers VI-II, or "cortical plate". Birthdating studies in rodents and carnivores revealed that subplate neurons are generated at the same time as Cajal-Retzius cells in the marginal zone (or future layer I), and prior to the birth of cortical plate neurons. 6. Subplate cells perform multiple developmental functions: they extend pioneer fi bers into the internal capsule and direct thalamo-cortical pathfi nding, serve as transient synaptic targets for thalamocortical fi bers, and provide a substantial glutamatergic input into the maturing cortical plate, helping in the establishment of ocular dominance columns in the primary visual cortex. As the cortical plate matures, many subplate neurons degenerate and undergo programmed cell death. The survivors continue into adult life as IN of the WM. 7. Subplate neurons are morphologically and neurochemically heterogeneous. The GABAergic subpopulations may express a variety of peptides such as neuropepide Y, somatostatin and/or cholecystokinin, or contain nitric oxide synthase. It
Seminars in Cell & Developmental Biology, 2017
The definition of a Cajal-Retzius neuron (CRN) is still controversial, in part possibly due to sp... more The definition of a Cajal-Retzius neuron (CRN) is still controversial, in part possibly due to species differences. We review the developmental history of CRN in human neocortex and focus on two main CRN family members, transient (t) and persisting (p) CRN. They share the expression of Reelin andTbr1, complemented by p73, calretinin, CXCR4 and NOS, but differ in their moment of appearance, fate and morphology. The distinctive feature of tCRN is the axon plexus in the lower third of the marginal zone, which innervates the apical dendritic tufts of pyramidal cells and may serve as a migration substrate and waiting compartment for interneurons descending from the subpial granular layer (SGL) into the cortical plate. Around midgestation, the SGL also gives rise to a transient interneuron type, the miniature neuron, that provides the GABAergic innervation of tCRN, which eventually, through diverse signaling pathways involving p73, contribute to the demise of tCRN and the breakdown of their plexus. The pCRN appear in the last trimester of gestation and may derive from committed CRN progenitors which migrate with the SGL from the periolfactory forebrain. They lack the horizontal CR plexus, and may be implicated in cortical folding, distribution of blood vessels, and plasticity of microcircuits in the molecular layer.
Cajal-Retzius (CR) cells of the mammalian neocortex co-express the extracellular matrix protein R... more 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.
p63 and p73, family members of the tumor suppressor p53, are critically involved in the life and ... more p63 and p73, family members of the tumor suppressor p53, are critically involved in the life and death of mammalian cells. They display high homology and may act in concert. The p73 gene is relevant for brain development, and p73-deficient mice display important malformations of the telencephalon. In turn, p63 is essential for the development of stratified epithelia and may also play a part in neuronal survival and aging. We show here that p63 and p73 are dynamically expressed in the embryonic and adult mouse and human telencephalon. During embryonic stages, Cajal-Retzius cells derived from the cortical hem co-express p73 and p63. Comparison of the brain phenotypes of p63-and p73-deficient mice shows that only the loss of p73 function leads to the loss of Cajal-Retzius cells, whereas p63 is apparently not essential for brain development and Cajal-Retzius cell formation. In postnatal mice, p53, p63, and p73 are present in cells of the subventricular zone (SVZ) of the lateral ventricle, a site of continued neurogenesis. The neurogenetic niche is reduced in size in p73-deficient mice, and the numbers of young neurons near the ventricular wall, marked with doublecortin, Tbr1 and calretinin, are dramatically decreased, suggesting that p73 is important for SVZ proliferation. In contrast to their restricted expression during brain development, p73 and p63 are widely detected in pyramidal neurons of the adult human cortex and hippocampus at protein and mRNA levels, pointing to a role of both genes in neuronal maintenance in adulthood.
Neurons of the subpial granular layer (SGL) in the human marginal zone (MZ) migrate tangentially ... more Neurons of the subpial granular layer (SGL) in the human marginal zone (MZ) migrate tangentially from the periolfactory subventricular zone all over the neocortex. After an immature stage, from 14 to 18 gestational weeks (GW), the SGL attains maximum prominence around midgestation. At 20-25 GW, a transient miniature cell type in the MZ expresses glutamate decarboxylase (GAD) and calretinin, and extends a varicose plexus surrounding somata of large transient Cajal-Retzius neurons (tCRN), potentially modulating their activity. The compact Reelin+ horizontal axon plexus of tCRN forms a transient interface between cortical plate and MZ; it may serve as a migration substrate for cortical interneurons, and attracting NPY+ fibers from the subplate. Around 30 GW, after the disappearance of SGL and tCRN, a population of persisting Cajal-Retzius neurons (pCRN) appears and remains into adult life. pCRNs express Reelin, Tbr1, calretinin, nitric oxide synthase, and the cytokine receptor CXCR4. They are characterized by subpial location, closeness to blood vessels, and aggregation in the walls of developing sulci. Unlike tCRNs, pCRNs do not develop a compact axon plexus in the lower MZ. Occasional mitoses in the midgestation SGL suggest that CRN progenitor cells may give rise to late-appearing pCRNs populating the definitive molecular layer.
bioRxiv (Cold Spring Harbor Laboratory), May 17, 2024
We acknowledge the Regionalverband Ruhr, Essen, Germany, for the interest in our work. We thank A... more We acknowledge the Regionalverband Ruhr, Essen, Germany, for the interest in our work. We thank Andrea Räk and Christian Riedel for technical support. We thank Prof. Schmelz and Prof. Engelhardt, University Mannheim, Germany, for donating the P5 piglet brain.
Knowledge on cortical development is based mainly on small rodents besides primates and carnivore... more Knowledge on cortical development is based mainly on small rodents besides primates and carnivores, all being altricial nestlings. Ungulates are precocial and born with nearly mature sensory and motor systems. Almost no information is available on ungulate brain development. Here, we analyzed European wild boar cortex development, focusing on the neuropeptide Y immunoreactive (NPY-ir) neuron system in dorsoparietal cortex from E35 to P30. Transient NPY-ir neuron types including archaic cells of the cortical plate and axonal loop cells of the subplate which appear by E60 concurrent with the establishment of the ungulate brain basic sulcal pattern. From E70, NPY-ir axons have an axon initial segment which elongates and shifts closer towards the axon's point of origin until P30. From E85 onwards (birth at E114), NPY-ir neurons in cortical layers form basket cell-like local and Martinotti cell-like ascending axonal projections. The mature NPY-ir pattern is recognizable at E110. Together, morphologies are conserved across species, but timing is not: in pig, the adult pattern largely forms prenatally.
A karyometric study of the medial and the lateral preoptic area of the male albino mouse has been... more A karyometric study of the medial and the lateral preoptic area of the male albino mouse has been carried out with the aid of a Leitz Image Analysis System (ASM). We have measured nuclear sizes of a control group of sixty mice, aged from the 5th to the 190th day of life. Another group of prepuberally castrated male mice, has been studied at the 25th, 35th, 45th, 55th and 85th postnatal day. The medial and the lateral preoptic area show different development patterns in the control group, and differential effects of castration in these zones were observed. The medial preoptic area, which has frequently been related to changes of sex hormone levels, experiments more important and statistically significant variations than the lateral preoptic area.
A karyometric study of the c~pendymal cells of the subcommissural organ (SCO) was made in male al... more A karyometric study of the c~pendymal cells of the subcommissural organ (SCO) was made in male albino mice castrated at 20 days and examined at 25, 35, 45, 55 and g5 days of life, and in control group.~ of the respective ages. The values of the nuclear areas and perimeters of SCO cells as well as those of the global volume of the SCO are significantly lower in the experimental groups, and the nuclear membrane shows less invaginations. No changes are observed after gonadectomy in the subjacent thalamic ependyma.
This review aims to provide examples of how both comparative and genetic analyses contribute to o... more 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-po...
Epilepsy and mental retardation, originally of unknown cause, are now known to result from many d... more 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...
The canonical view of neuronal function is that inputs are received by dendrites and somata, beco... more The canonical view of neuronal function is that inputs are received by dendrites and somata, become integrated in the somatodendritic compartment and upon reaching a sufficient threshold, generate axonal output with axons emerging from the cell body. The latter is not necessarily the case. Instead, axons may originate from dendrites. The terms “axon carrying dendrite” (AcD) and “AcD neurons” have been coined to describe this feature. Here, we report on the diversity of axon origins in neocortical pyramidal cells. We found that in non-primates (rodent, cat, ferret, pig), 10-21% of pyramidal cells of layers II-VI had an AcD. In marked contrast, in macaque and human, this proportion was lower, and it was particularly low for supragranular neurons. Unexpectedly, pyramidal cells in the white matter of postnatal cat and aged human cortex exhibit AcDs to much higher percentages. In rodent hippocampus, AcD cells are functionally ‘privileged’, since inputs here can circumvent somatic integra...
The human insula is a key node in a neuronal network which integrates interoceptive stimuli from ... more The human insula is a key node in a neuronal network which integrates interoceptive stimuli from the own body, and exteroceptive stimuli from the environment, and thus maintains the autonomic, emotional and socio-cognitive homeostasis of the body. In the last years, the insula has come into the focus of attention. Comparative anatomical studies showed that in many species the insula forms the lateral edge of the cortex. Very little is known about the prenatal development of the human insula, which is the first cortical region to mature. The origin of the pyramidal neurons for the insula is a small sector of the proliferating ventricular/subventricular zone at the cortico-striatal boundary (CSB). The CSB contains the radial glia cells, which are stem cells and give rise to a dense fascicle of radial glia processes. This fascicle traverses the external capsule and serves as a migration substrate for the neuroblasts on their way from the CSB into the insula. Around the 10/11th week of ...
Proceedings of the National Academy of Sciences, 1998
Behavioral and neurophysiological studies suggest that skill learning can be mediated by discrete... more Behavioral and neurophysiological studies suggest that skill learning can be mediated by discrete, experience-driven changes within specific neural representations subserving the performance of the trained task. We have shown that a few minutes of daily practice on a sequential finger opposition task induced large, incremental performance gains over a few weeks of training. These gains did not generalize to the contralateral hand nor to a matched sequence of identical component movements, suggesting that a lateralized representation of the learned sequence of movements evolved through practice. This interpretation was supported by functional MRI data showing that a more extensive representation of the trained sequence emerged in primary motor cortex after 3 weeks of training. The imaging data, however, also indicated important changes occurring in primary motor cortex during the initial scanning sessions, which we proposed may reflect the setting up of a task-specific motor processi...
CeLL CyCLe news & views 1186 Cell Cycle volume 10 issue 8 Mucous epithelia and their glands show ... more CeLL CyCLe news & views 1186 Cell Cycle volume 10 issue 8 Mucous epithelia and their glands show continuous self-renewal, from multipotent somatic (adult) stem cells as well as from a pool of transit-amplifying cells that gradually differentiate and migrate to their final destinations. The mammalian stomach, along with the intestine, is one of the organs with the highest cellular turnover. The gastric regeneration dynamics were established in detail in the mouse by Leblond and his coworkers about 20 years ago. 1 The morphology and the self-renewal of the human stomach differ in important details from the murine sytem. 2 Histologically, the human gastric mucosa, which is of endodermal origin, is divided into three zones: the cardiac zone, the fundus/
Cajal-Retzius (CR) cells are the most significant source of reelin, an extracellular matrix glyco... more Cajal-Retzius (CR) cells are the most significant source of reelin, an extracellular matrix glycoprotein essential for cortical development. Strategically located in the marginal zone, CR cells control radial migration and laminar positioning of pyramidal neurons of the cortical plate. They degenerate and undergo cell death when cortical migration is completed. In human cortex development, reelin-expressing CR cells are already present in the early preplate, and continue to increase in number after the appearance of the cortical plate. In the course of the first half of gestation, the reelin signal in the marginal zone undergoes a huge amplification in parallel with the growth of the cortical plate and the expansion of the cortical surface. A significant source of CR cells is the cortical hem, a putative signalling centre at the interface of the prospective hippocampus and the choroid plexus. Hem-derived CR cells co-express reelin and p73, a transcription factor of the p53-family. They form the predominant CR cell population of the human neocortex. Characteristically, CR cells express the anti-apoptotic isoform DeltaNp73 which may be responsible for the protracted lifespan of human CR cells and the morphological differentiation of their axonal plexus. This dense fibre plexus, absent in lower mammals, amplifies the reelin-signal and establishes a physical boundary between the cortical plate and the marginal zone. In this review, we analyze the multiple sources of reelin ⁄ p73 positive CR cells at the interface of various telencephalic centres and the choroid plexus of the lateral ventricles. Additional populations of CR cells may derive from the thalamic eminence in the ventral thalamus and from the strionuclear neuroepithelium, or 'amygdalar hem'. Comparative studies in a variety of species indicate that the cortical hem is the main origin of CR cells destined for the neocortex, and is most highly developed in the human brain. The close association between cortical hem and choroid plexus suggests a concerted role in the evolutionary increase of CR cells, amplification of the reelin signal in the marginal zone, and cortical expansion.
of the gyri, where radial fi ber fascicles intermingle with radial rows of layer VIb neurons and ... more of the gyri, where radial fi ber fascicles intermingle with radial rows of layer VIb neurons and IN seem to be continuous with neurons of layer VIb. 3. The highest density of IN is in the WM immediately subjacent to the gray matter, in the zone that contains the association or "U" fi bers of the cortical convolutions, and then gradually decreases with increasing distance from the gray matter. Very few neurons lie among the long fi ber tracts in the deep WM, such as internal capsule, superior and inferior longitudinal fasciculi, or corpus callosum. However, there is no sharp boundary between the superfi cial WM, rich in IN, and the deep WM, where IN are sparse. There may also be regional differences in the density of IN, with lowest numbers in the visual cortex, and higher numbers in the frontal and prefrontal cortex. 4. The IN display a variety of morphologies ranging from pyramidal-like to bipolar and multipolar. They can be classifi ed into the two main neuronal categories also present in the gray matter, namely excitatory glutamatergic cells and inhibitory GABAergic neurons. 5. IN of the cortical WM are often referred to as "subplate" cells. During development, the subplate is a transient cell compartment just below the future layers VI-II, or "cortical plate". Birthdating studies in rodents and carnivores revealed that subplate neurons are generated at the same time as Cajal-Retzius cells in the marginal zone (or future layer I), and prior to the birth of cortical plate neurons. 6. Subplate cells perform multiple developmental functions: they extend pioneer fi bers into the internal capsule and direct thalamo-cortical pathfi nding, serve as transient synaptic targets for thalamocortical fi bers, and provide a substantial glutamatergic input into the maturing cortical plate, helping in the establishment of ocular dominance columns in the primary visual cortex. As the cortical plate matures, many subplate neurons degenerate and undergo programmed cell death. The survivors continue into adult life as IN of the WM. 7. Subplate neurons are morphologically and neurochemically heterogeneous. The GABAergic subpopulations may express a variety of peptides such as neuropepide Y, somatostatin and/or cholecystokinin, or contain nitric oxide synthase. It
Seminars in Cell & Developmental Biology, 2017
The definition of a Cajal-Retzius neuron (CRN) is still controversial, in part possibly due to sp... more The definition of a Cajal-Retzius neuron (CRN) is still controversial, in part possibly due to species differences. We review the developmental history of CRN in human neocortex and focus on two main CRN family members, transient (t) and persisting (p) CRN. They share the expression of Reelin andTbr1, complemented by p73, calretinin, CXCR4 and NOS, but differ in their moment of appearance, fate and morphology. The distinctive feature of tCRN is the axon plexus in the lower third of the marginal zone, which innervates the apical dendritic tufts of pyramidal cells and may serve as a migration substrate and waiting compartment for interneurons descending from the subpial granular layer (SGL) into the cortical plate. Around midgestation, the SGL also gives rise to a transient interneuron type, the miniature neuron, that provides the GABAergic innervation of tCRN, which eventually, through diverse signaling pathways involving p73, contribute to the demise of tCRN and the breakdown of their plexus. The pCRN appear in the last trimester of gestation and may derive from committed CRN progenitors which migrate with the SGL from the periolfactory forebrain. They lack the horizontal CR plexus, and may be implicated in cortical folding, distribution of blood vessels, and plasticity of microcircuits in the molecular layer.
Cajal-Retzius (CR) cells of the mammalian neocortex co-express the extracellular matrix protein R... more 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.
p63 and p73, family members of the tumor suppressor p53, are critically involved in the life and ... more p63 and p73, family members of the tumor suppressor p53, are critically involved in the life and death of mammalian cells. They display high homology and may act in concert. The p73 gene is relevant for brain development, and p73-deficient mice display important malformations of the telencephalon. In turn, p63 is essential for the development of stratified epithelia and may also play a part in neuronal survival and aging. We show here that p63 and p73 are dynamically expressed in the embryonic and adult mouse and human telencephalon. During embryonic stages, Cajal-Retzius cells derived from the cortical hem co-express p73 and p63. Comparison of the brain phenotypes of p63-and p73-deficient mice shows that only the loss of p73 function leads to the loss of Cajal-Retzius cells, whereas p63 is apparently not essential for brain development and Cajal-Retzius cell formation. In postnatal mice, p53, p63, and p73 are present in cells of the subventricular zone (SVZ) of the lateral ventricle, a site of continued neurogenesis. The neurogenetic niche is reduced in size in p73-deficient mice, and the numbers of young neurons near the ventricular wall, marked with doublecortin, Tbr1 and calretinin, are dramatically decreased, suggesting that p73 is important for SVZ proliferation. In contrast to their restricted expression during brain development, p73 and p63 are widely detected in pyramidal neurons of the adult human cortex and hippocampus at protein and mRNA levels, pointing to a role of both genes in neuronal maintenance in adulthood.
Neurons of the subpial granular layer (SGL) in the human marginal zone (MZ) migrate tangentially ... more Neurons of the subpial granular layer (SGL) in the human marginal zone (MZ) migrate tangentially from the periolfactory subventricular zone all over the neocortex. After an immature stage, from 14 to 18 gestational weeks (GW), the SGL attains maximum prominence around midgestation. At 20-25 GW, a transient miniature cell type in the MZ expresses glutamate decarboxylase (GAD) and calretinin, and extends a varicose plexus surrounding somata of large transient Cajal-Retzius neurons (tCRN), potentially modulating their activity. The compact Reelin+ horizontal axon plexus of tCRN forms a transient interface between cortical plate and MZ; it may serve as a migration substrate for cortical interneurons, and attracting NPY+ fibers from the subplate. Around 30 GW, after the disappearance of SGL and tCRN, a population of persisting Cajal-Retzius neurons (pCRN) appears and remains into adult life. pCRNs express Reelin, Tbr1, calretinin, nitric oxide synthase, and the cytokine receptor CXCR4. They are characterized by subpial location, closeness to blood vessels, and aggregation in the walls of developing sulci. Unlike tCRNs, pCRNs do not develop a compact axon plexus in the lower MZ. Occasional mitoses in the midgestation SGL suggest that CRN progenitor cells may give rise to late-appearing pCRNs populating the definitive molecular layer.
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Papers by Gundela Meyer