Neuroscience. Genetic control of cortical convolutions.
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Animals↗
Biomedical subjects
Pasko Rakic
Publications and source records attributed to Pasko Rakic.
Novel neuronal phenotypes from neural progenitor cells.
We report the first isolation of progenitor cells from the hypothalamus, a derivative of the embryonic basal plate that does not exhibit neurogenesis postnatally. Neurons derived from hypothalamic progenitor cells were compared with those derived from progenitor cultures of hippocampus, an embryonic alar plate derivative that continues to support neurogenesis in vivo into adulthood. Aside from their different embryonic origins and their different neurogenic potential in vivo, these brain regions were chosen because they are populated with cells of three different categories: Category I cells are generated in both hippocampus and hypothalamus, Category II cells are generated in the hypothalamus but are absent from the hippocampus, and Category III is a cell type generated in the olfactory placode that migrates into the hypothalamus during development. Stem-like cells isolated from other brain regions, with the ability to generate neurons and glia, produce neurons of several phenotypes including gabaergic, dopaminergic, and cholinergic lineages. In the present study, we extended our observations into neuroendocrine phenotypes. The cultured neural precursors from 7-week-old rat hypothalamus readily generated neuropeptide-expressing neurons. Hippocampal and hypothalamic progenitor cultures converged to indistinguishable populations and produced neurons of all three categories, confirming that even short-term culture confers or selects for immature progenitors with enough plasticity to elaborate neuronal phenotypes usually inhibited in vivo by the local microenvironment. The range of phenotypes generated from neuronal precursors in vitro now includes the peptides found in the neuroendocrine system: corticotropin-releasing hormone, growth hormone-releasing hormone, gonadotropin-releasing hormone, oxytocin, somatostatin, thyrotropin-releasing hormone, and vasopressin.
Animals↗
Neuroscience: immigration denied.
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Animals↗
Early serotonergic projections to Cajal-Retzius cells: relevance for cortical development.
Although the serotonergic system plays an important role in various neurological disorders, the role of early serotonergic projections to the developing cerebral cortex is not well understood. Because serotonergic fibers enter the marginal zone (MZ) before birth, it has been suggested that they may influence cortical development through synaptic contacts with Cajal-Retzius (CR) cells. We used immunohistochemistry combined with confocal and electron microscopy to show that the earliest serotonergic projections to the MZ form synaptic contacts with the somata and proximal dendrites of CR cells as early as embryonic day 17. To elucidate the functional significance of these early serotonergic contacts with CR cells, we perturbed their normal development by injecting pregnant mice with 5-methoxytryptamine. Lower reelin levels were detected in the brains of newborn pups from the exposed animals. Because reelin plays an important role in the cortical laminar and columnar organization during development, we killed some pups from the same litters on postnatal day 7 and analyzed their presubicular cortex. We found that the supragranular layers of the presubicular cortex (which normally display a visible columnar deployment of neurons) were altered in the treated animals. Our results suggest a mechanism of how serotonergic abnormalities during cortical development may disturb the normal cortical organization; and, therefore, may be relevant for understanding neurological disorders in which abnormalities of the serotonergic system are accompanied by cortical pathology (such as autism).
5-Methoxytryptamine↗
SPARC-like 1 regulates the terminal phase of radial glia-guided migration in the cerebral cortex.
Differential adhesion between migrating neurons and transient radial glial fibers enables the deployment of neurons into appropriate layers in the developing cerebral cortex. The identity of radial glial signals that regulate the termination of migration remains unclear. Here, we identified a radial glial surface antigen, SPARC (secreted protein acidic and rich in cysteine)-like 1, distributed predominantly in radial glial fibers passing through the upper strata of the cortical plate (CP) where neurons end their migration. Neuronal migration and adhesion assays indicate that SPARC-like 1 functions to terminate neuronal migration by reducing the adhesivity of neurons at the top of the CP. Cortical neurons fail to achieve appropriate positions in the absence of SPARC-like 1 function in vivo. Together, these data suggest that antiadhesive signaling via SPARC-like 1 on radial glial cell surfaces may enable neurons to recognize the end of migration in the developing cerebral cortex.
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JNK-mediated induction of cyclooxygenase 2 is required for neurodegeneration in a mouse model of Parkinson's disease.
Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of dopamine-containing neurons, but the molecular pathways underlying its pathogenesis remain uncertain. Here, we show that by eliminating c-Jun N-terminal kinases (JNKs) we can prevent neurodegeneration and improve motor function in an animal model of PD. First, we found that c-Jun is activated in dopaminergic neurons from PD patients and in the 1-methyl-4-phenyl-1,2,4,6-tetrahydropyridine (MPTP) mouse model of PD. Examination of various JNK-deficient mice shows that both JNK2 and JNK3, but not JNK1, are required for MPTP-induced c-Jun activation and dopaminergic cell demise. Furthermore, we have identified cyclooxygenase (COX) 2 as a molecular target of JNK activation and demonstrated that COX-2 is indispensable for MPTP-induced dopaminergic cell death. Our data revealed that JNK2- and JNK3-induced COX-2 may be a principle pathway responsible for neurodegeneration in PD.
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A critical role of neural-specific JNK3 for ischemic apoptosis.
c-Jun N-terminal kinase (JNK) signaling is an important contributor to stress-induced apoptosis, but it is unclear whether JNK and its isoforms (JNK1, JNK2, and JNK3) have distinct roles in cerebral ischemia. Here we show that JNK1 is the major isoform responsible for the high level of basal JNK activity in the brain. In contrast, targeted deletion of Jnk3 not only reduces the stress-induced JNK activity, but also protects mice from brain injury after cerebral ischemia-hypoxia. The downstream mechanism of JNK3-mediated apoptosis may include the induction of Bim and Fas and the mitochondrial release of cytochrome c. These results suggest that JNK3 is a potential target for neuroprotection therapies in stroke.
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Phosphatidylserine receptor is required for clearance of apoptotic cells.
Cells undergoing apoptosis during development are removed by phagocytes, but the underlying mechanisms of this process are not fully understood. Phagocytes lacking the phosphatidylserine receptor (PSR) were defective in removing apoptotic cells. Consequently, in PSR-deficient mice, dead cells accumulated in the lung and brain, causing abnormal development and leading to neonatal lethality. A fraction of PSR knockout mice manifested a hyperplasic brain phenotype resembling that of mice deficient in the cell death-associated genes encoding Apaf-1, caspase-3, and caspase-9, which suggests that phagocytes may also be involved in promoting apoptosis. These data demonstrate a critical role for PSR in early stages of mammalian organogenesis and suggest that this receptor may be involved in respiratory distress syndromes and congenital brain malformations.
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Four-dimensional migratory coordinates of GABAergic interneurons in the developing mouse cortex.
We have used time-lapse multiphoton microscopy to map the migration and settling pattern of GABAergic interneurons that originate in the ganglionic eminence of the ventral forebrain and incorporate into the neocortex of the cerebral hemispheres. Imaging of the surface of the cerebral hemispheres in both explant cultures and brains of living mouse embryos revealed that GABAergic interneurons migrating within the marginal zone originate from three different sources and migrate via distinct and independent streams. After reaching their areal destination, interneurons descend into the underlying cortex to assume positions with isochronically generated, radially derived neurons. The dynamics and pattern of cell migration in the marginal zone (see movies, available at www.jneurosci.org) suggest that the three populations of interneurons respond selectively to distinct local cues for directing their migration to the appropriate areas and layers of the neocortex. This approach opens a new avenue for study of normal and abnormal neuronal migration in their native environment and indicate that interneurons have specific programs for their areal and laminar deployment.
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Mitotic spindle rotation and mode of cell division in the developing telencephalon.
The mode of neural stem cell division in the forebrain proliferative zones profoundly influences neocortical growth by regulating the number and diversity of neurons and glia. Long-term time-lapse multiphoton microscopy of embryonic mouse cortex reveals new details of the complex three-dimensional rotation and oscillation of the mitotic spindle before stem cell division. Importantly, the duration and amplitude of spindle movement predicts and specifies the eventual mode of mitotic division. These technological advances have provided dramatic data and insights into the kinetics of neural stem cell division by elucidating the involvement of spindle rotation in selection of the cleavage plane and the mode of neural stem cell division that together determine the size of the mammalian neocortex.
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Elusive radial glial cells: historical and evolutionary perspective.
Since the discovery of radial glial cells in the human fetal forebrain, this specialized cellular population has been identified in most regions of the vertebrate brain during restricted developmental periods. However, their size, longevity, and significance for guiding migrating neurons have increased with the evolutionary expansion of the mammalian neocortex, reaching a peak in the gyrencephalic human forebrain. The phenotypic distinction of radial glial cells from the more specialized neuronal progenitors in the proliferative zones and from the migrating neurons in the intermediate zone of the primate fetal forebrain, based initially on morphological criteria, has been supported by their ultrastructural, molecular, and physiological characteristics. In addition, modern in vivo and in vitro approaches revealed that these specialized embryonic cells can also generate neuronal cell lines, which either immediately, or after several divisions, migrate along radial shaft processes of the mother cells that span the expanding and convoluted cerebral wall. The multiple functions of radial glial cells and their species-specific adaptations indicate a pivotal role in evolution, development, and pathology of the cerebral neocortex.
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Developmental and evolutionary adaptations of cortical radial glia.
The concept of transient radial glial cells, based originally on observations made on the human fetal brain stained with the classical Golgi silver impregnation method, has been evolving with the application of advanced methods of anatomy, molecular biology and genetics. In addition to providing scaffolding for migration and placement of neurons, these specialized cells can generate neuronal cell lineage that either immediately, or following multiple divisions, migrate along the elongated radial process of the mother cell. Comparative analysis of the data on emergence, function and morphogenetic transformation of radial glial cells in the mouse, macaque and human embryonic cerebral wall reveals both similarities as well as species-specific differences in the timing, sequence, biochemical composition and level of phenotypic differentiation that provide insight into cortical development and evolution, as well as into pathogenesis of genetic and acquired cortical abnormalities.
Adaptation, Physiological↗
Craniofacial dysmorphogenesis in fetally irradiated nonhuman primates: implications for the neurodevelopmental hypothesis of schizophrenia.
BACKGROUND: Craniofacial abnormalities arising from gestational disturbances have been documented in some schizophrenic patients. Reduction of thalamic neurons, a key feature of the neuropathology of schizophrenia, could also have a prenatal origin via disruption of thalamic neurogenesis. This study investigates whether craniofacial dysmorphology and thalamic neuron loss might be associated manifestations of a disruption in embryonic development. METHODS: Thalamic neurons were deleted by exposing fetal macaques to x-rays during thalamic genesis (E33-42). Another group of macaques was irradiated after thalamic genesis (E70-81). Body, head, and facial measurements were obtained from the early irradiated (EX), late irradiated (LX), and control animals at adulthood. RESULTS: Head width, distance between outer eye edges, and ear width were smaller in EX macaques compared with control animals. The LX macaques exhibited only reduced ear width compared with control animals. CONCLUSIONS: These findings indicate that certain features of thalamic neuropathology and craniofacial dysmorphogenesis observed in schizophrenic patients may have a common etiology.
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Origin of GABAergic neurons in the human neocortex.
The mammalian neocortex contains two major classes of neurons, projection and local circuit neurons. Projection neurons contain the excitatory neurotransmitter glutamate, while local circuit neurons are inhibitory, containing GABA. The complex function of neocortical circuitry depends on the number and diversity of GABAergic (gamma-aminobutyric-acid-releasing) local circuit neurons. Using retroviral labelling in organotypic slice cultures of the embryonic human forebrain, we demonstrate the existence of two distinct lineages of neocortical GABAergic neurons. One lineage expresses Dlx1/2 and Mash1 transcription factors, represents 65% of neocortical GABAergic neurons in humans, and originates from Mash1-expressing progenitors of the neocortical ventricular and subventricular zone of the dorsal forebrain. The second lineage, characterized by the expression of Dlx1/2 but not Mash1, forms around 35% of the GABAergic neurons and originates from the ganglionic eminence of the ventral forebrain. We suggest that modifications in the expression pattern of transcription factors in the forebrain may underlie species-specific programmes for the generation of neocortical local circuit neurons and that distinct lineages of cortical interneurons may be differentially affected in genetic and acquired diseases of the human brain.
Basic Helix-Loop-Helix Proteins↗
Abnormalities of thalamic volume and shape detected in fetally irradiated rhesus monkeys with high dimensional brain mapping.
BACKGROUND: Prior research has indicated neuroanatomical abnormalities of the thalamus in schizophrenia. To study the possible pathogenesis, an animal model of neurodevelopmental thalamic damage has been developed by applying low-dose radiation to rhesus monkeys in early gestation. Irradiated monkeys sacrificed as infants demonstrate neuronal losses in specific thalamic nuclei and decreases in cortical neuropil. METHODS: Magnetic resonance scans were collected in adult Rhesus monkeys exposed to irradiation during thalamic neurogenesis (E33-42), after thalamic neurogenesis (E70-81), and in nonirradiated control animals. High dimensional brain mapping was used to compare thalamic volumes and shape characteristics in the three groups of animals. RESULTS: Animals exposed to irradiation at E33-42 showed a significant bilateral loss of thalamic volumes (> 20%) compared with controls and with animals irradiated at E70-81 when total brain volume was used as a covariate in the analysis. Thalamic volume loss was associated with a nonuniform deformation of thalamic shape. CONCLUSIONS: A first-trimester, neurodevelopmental insult in the nonhuman primate during thalamic neurogenesis produces a complex pattern of thalamic volume loss and shape deformation in adulthood. Low-dose irradiation of the fetal primate may be useful for modeling key features of the pathology described in schizophrenic patients.
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The gamma-secretase-generated intracellular domain of beta-amyloid precursor protein binds Numb and inhibits Notch signaling.
The beta-amyloid precursor protein (APP) and the Notch receptor undergo intramembranous proteolysis by the Presenilin-dependent gamma-secretase. The cleavage of APP by gamma-secretase releases amyloid-beta peptides, which have been implicated in the pathogenesis of Alzheimer's disease, and the APP intracellular domain (AID), for which the function is not yet well understood. A similar gamma-secretase-mediated cleavage of the Notch receptor liberates the Notch intracellular domain (NICD). NICD translocates to the nucleus and activates the transcription of genes that regulate the generation, differentiation, and survival of neuronal cells. Hence, some of the effects of APP signaling and Alzheimer's disease pathology may be mediated by the interaction of APP and Notch. Here, we show that membrane-tethered APP binds to the cytosolic Notch inhibitors Numb and Numb-like in mouse brain lysates. AID also binds Numb and Numb-like, and represses Notch activity when released by APP. Thus, gamma-secretase may have opposing effects on Notch signaling; positive by cleaving Notch and generating NICD, and negative by processing APP and generating AID, which inhibits the function of NICD.
Amyloid Precursor Protein Secretases↗
Adult neurogenesis in mammals: an identity crisis.
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Aging↗
Evolving concepts of cortical radial and areal specification.
The fundamental principles of cortical organization and its development, postulated by Santiago Ramón y Cajal at the turn of the century, based on his exquisite observations and ingenious interpretation of neuronal assemblies impregnated with the Golgi method, are being expanded with the application of advanced methods of anatomy, molecular biology and genetics. In this chapter, I will focus on the concept of columnar organization and areal specifications of the cerebral cortex that has served as a useful framework for understanding its development as well as its function as an evolving organ of thought.
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