Perinatal brain damage, cortical reorganization (acquired cortical dysplasias), and epilepsy.
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Adolescent↗
Biomedical subjects
M Marín-Padilla
Publications and source records attributed to M Marín-Padilla.
Early development and composition of the human primordial plexiform layer: An immunohistochemical study.
The early expression of reelin, calcium-binding proteins (calretinin, calbindin, and parvalbumin), and neurofilament proteins have been explored in the developing central nervous system of human embryos and fetuses during the first trimester of gestation. Our objective has been to determine further the nature, developmental roles, and contributions of the early neurons and fibers of the original subpial neuropil, i.e., the primordial plexiform layer (PPL). In young embryos (4-5 weeks old), neurofilament protein-labeled fibers run through the subpial neuropil of the caudal portion of the neural tube, reaching the mesencephalon rostrally. At this age, calretinin-immunoreactive and calbindin-immunoreactive neurons are also found among cells already detached from the ventricular zone. The expression of neurofilament protein, calretinin, and calbindin follows an ascending caudorostral gradient, reaching the cerebral vesicles by the 6th-7th week of gestation. In the cerebral cortex, this timing coincides with the initial expression of reelin in the PPL. The reelin immunoreactivity throughout the most superficial cellular population of the cortical PPL supports the early genesis of Cajal-Retzius cells, around the 6th week of gestation. After the splitting of the PPL by the formation of the cortical plate (7-8 weeks of gestation), reelin-immunoreactive cells remain only in the newly established layer I. This study proposes that an initial PPL may be a universal feature of the developing central nervous system.
Calbindin 2↗
Core-binding factor: a central player in hematopoiesis and leukemia.
Consistent chromosomal rearrangements are found in a large number of hematopoietic tumors. In many cases, these rearrangements disrupt genes whose normal function is required for the proper development of blood cells. Excellent examples are the chromosomal rearrangements t(8;21)(q22;q22), t(12;21)(p13;q22), and inv(16)(p13q22) that disrupt two of the genes encoding a small family of heterodimeric transcription factors, core-binding factors (CBFs). CBFs consist of a DNA-binding CBFalpha subunit and a non-DNA-binding CBFbeta subunit. The t(8;21), associated with de novo acute myeloid leukemias, disrupts the CBFA2 (AML1) gene, which encodes a DNA-binding CBFalpha subunit. The t(12;21), the most common translocation in pediatric acute lymphocytic leukemias, also disrupts CBFA2. The CBFB gene, which encodes the non-DNA-binding subunit of the CBFs, is disrupted by the inv(16) in de novo acute myeloid leukemias. All chromosomal rearrangements involving the CBFA2 and CBFB genes create chimeric proteins, two of which have been unequivocally demonstrated to function as transdominant negative inhibitors of CBF function. Both the Cbfa2 and Cbfb genes are essential for normal hematopoiesis in mice, because homozygous disruption of either gene blocks definitive hematopoiesis. Recent data suggest that Cbfa2 and Cbfb are required for the emergence of definitive hematopoietic stem cells in the embryo from a putative definitive hemangioblast precursor. The transdominant negative inhibitor of CBF created by the inv(16), when present from the beginning of embryogenesis, also blocks the emergence of definitive hematopoietic cells in the embryo. On the other hand, chromosomal translocations involving the CBFA2 and CBFB genes in leukemias block hematopoiesis at later steps. This may reflect a difference in the timing at which translocations are acquired in the leukemias, which presumably is subsequent to emergence of the definitive hematopoietic stem cell. The cumulative data suggest that although the earliest requirement for Cbfa2 and Cbfb is for emergence of definitive hematopoietic stem cells, both genes are also required at later stages in the differentiation of some hematopoietic lineages.
Animals↗
Developmental neuropathology and impact of perinatal brain damage. III: gray matter lesions of the neocortex.
The evolving neuropathology of primarily undamaged cortical regions adjacent to the injured site has been studied in 36 infants who survived a variety of perinatally acquired encephalopathies (microgyrias, ulegyrias, multicystic encephalopathies, porencephalies, and hydranencephalies) and later died of unrelated causes. Their survival times range from hours, days, weeks, or months, to several years. Ten of these children developed epilepsy, 2 developed cerebral palsy, and several were neurologically and mentally impaired. In all cases studied, the undamaged cortex adjacent to the injured site survives, retains its intrinsic vasculature, and is capable of continuing differentiation. However, its postinjury development is characterized by progressive alterations compatible with acquired cortical dysplasia that affects the structural and functional differentiation of its neurons, synaptic profiles, fiber distribution, glial elements, and vasculature. The synaptic profiles of many neurons are transformed by an increased number of intrinsic loci that replace extrinsic ones vacated by the destruction of afferent fibers. The intrinsic fibers of layer I and some Cajal-Retzius cells survive even in severe lesions and may be capable of interconnecting cortical regions that have lost other type of connections. Some intrinsic neurons undergo postinjury structural and functional hypertrophy, acquire new morphologic and functional features, and achieve a large size (meganeurons). Probably, these meganeurons acquire their structural and functional hypertrophy by partial endomitotic DNA and/or RNA reduplication (polyploidy). These postinjury alterations are not static but ongoing processes that continue to affect the structural and functional differentiation of the still developing cortex and may eventually influence the neurologic and cognitive maturation of affected children. This study proposes that, in acquired encephalopathies, the progressive postinjury reorganization of the undamaged cortex and its consequences (acquired cortical dysplasia), rather than the original lesion, represent the main underlying mechanism in the pathogenesis of ensuing neurological sequelae, such as, epilepsy, cerebral palsy, dyslexia, cognitive impairment, and/or poor school performance.
Acute Disease↗
Cbfa2 is required for the formation of intra-aortic hematopoietic clusters.
Cbfa2 (AML1) encodes the DNA-binding subunit of a transcription factor in the small family of core-binding factors (CBFs). Cbfa2 is required for the differentiation of all definitive hematopoietic cells, but not for primitive erythropoiesis. Here we show that Cbfa2 is expressed in definitive hematopoietic progenitor cells, and in endothelial cells in sites from which these hematopoietic cells are thought to emerge. Endothelial cells expressing Cbfa2 are in the yolk sac, the vitelline and umbilical arteries, and in the ventral aspect of the dorsal aorta in the aorta/genital ridge/mesonephros (AGM) region. Endothelial cells lining the dorsal aspect of the aorta, and elsewhere in the embryo, do not express Cbfa2. Cbfa2 appears to be required for maintenance of Cbfa2 expression in the endothelium, and for the formation of intra-aortic hematopoietic clusters from the endothelium.
Animals↗
Persistence of Cajal-Retzius cells in the adult human cerebral cortex. An immunohistochemical study.
The presence of Cajal-Retzius cells in the adult human prefrontal and visual cortices has been demonstrated with calcium binding protein immunocytochemistry and NADPH-diaphorase histochemistry. These cells expressed parvalbumin, calbindin and calretinin calcium binding proteins and displayed NADPH-diaphorase enzyme activity. The three basic morphological profiles-horizontal, pyriform and multipolar-were observed. The morphologies of labelled cells resembled those of neurons observed in Golgi studies of the human cerebral cortex. The presence of calcium binding proteins and NADPH-diaphorase in these cells suggests a possible inhibitory role as GABAergic neurons. The persistence of Cajal-Retzius cells in the adult cerebral cortex supports the idea that they undergo developmental dilution rather than postnatal degeneration.
Adult↗
Cajal-Retzius cells and the development of the neocortex.
The dual origin, structural organization, and evolving ascending stratification of the mammalian neocortex are explored from a developmental perspective. Layer I and subplate (layer VII) zone of the neocortex evolve first from a primordial plexiform neuropil that is established throughout the non-olfactory telencephalon and that is common to amphibians, reptiles and mammals. The remaining laminations (strata) of the neocortex evolve later, between layer I and the subplate zone, from the cortical plate (CP), which represents a multilayered mammalian evolutionary feature. The attraction of CP neurons towards layer I, their progressive ascending (inside-out) placement, common early differentiation stage (regardless of size, location, cortical depth, or eventual functional role, or all of these), and the unique morphologic features of its pyramidal neuron are developmental processes controlled by layer I and its Cajal-Retzius cells. Based on the role of these early neurons and of layer I, a new theory of neocortical cytoarchitectonics and nomenclature is proposed to explain the basic structural and functional organization of the mammalian neocortex, the morphology of its pyramidal cells, and the addition of new pyramidal cell strata that characterize its phylogenetic evolution.
Animals↗
Embryonic lethality and impairment of haematopoiesis in mice heterozygous for an AML1-ETO fusion gene.
Acute myeloid leukaemia (AML) is a major haematopoietic malignancy characterized by the proliferation of a malignant clone of myeloid progenitor cells. A reciprocal translocation, t(8;21)(q22;q22), observed in the leukaemic cells of approximately 40% of patients with the M2 subtype of AML disrupts both the AML1 (CBFA2) gene on chromosome 21 and the ETO (MTG8) gene on chromosome 8 (refs 3-5). A chimaeric protein is synthesized from one of the derivative chromosomes that contains the N terminus of the AML1 transcription factor, including its DNA-binding domain, fused to most of ETO, a protein of unknown function. We generated mice that mimic human t(8;21) with a "knock-in' strategy. Mice heterozygous for an AML1-ETO allele (AML1-ETO/+) die in midgestation from haemorrhaging in the central nervous system and exhibit a severe block in fetal liver haematopoiesis. This phenotype is very similar to that resulting from homozygous disruption of the AML1 (Cbfa2) or Cbfb genes, indicating that AML1-ETO blocks normal AML1 function. However, yolk sac cells from AML1-ETO/+ mice differentiated into macrophages in haematopoietic colony forming unit (CFU) assays, unlike Cbfa2-/- or Cbfb-/-cells, which form no colonies in vitro. This indicates that AML1-ETO may have other functions besides blocking wild-type AML1, a property that may be important in leukaemogenesis.
Animals↗
Developmental neuropathology and impact of perinatal brain damage. II: white matter lesions of the neocortex.
The neuropathology and developmental impact of acute, subacute, and chronic white matter lesions has been studied in infants who survived (days, weeks, months, or years) this type of perinatal brain damage. The study emphasizes the survival of the developing gray matter overlying extensive white matter lesions (multicystic encephalopathy, porencephaly, and hydranencephaly ex-vacuo). Although partially isolated from afferent inputs (corticipetal fiber destruction) and unable to reach other cortical centers (corticofugal fiber destruction), this overlying gray matter is able to survive because neither its independent leptomeningeal blood supply nor its intrinsic anastomotic vasculature are affected by the underlying lesion. Moreover, the postinjury structural and functional development of this partially isolated gray matter is altered. Some of its axotomized pyramidal neurons are transformed into local-circuit interneurons, some of its interneurons are structurally and functionally enlarged (hypertrophy), and its intracortical neuropil (deprived of afferent synaptic terminals) increases by an expansion of intrinsic terminals (hypertrophy). An attempt has been made to correlate these postinjury alterations with the pathogenesis of the ensuing neurologic sequelae (7 infants develop epilepsy). The study proposes that neurological sequelae (e.g. epilepsy and cerebral palsy) following perinatal white matter lesions are a direct consequence of the postinjury gray matter transformations.
Brain Damage, Chronic↗
[Pathology and pathogenesis of secondary epilepsy to hypoxic-ischemic encephalopathies].
The neuropathology of haemorrhagic and hypoxic-ischaemic perinatal encephalopathies and their effect on the post-natal development of the brain, has been studied in children who survived with these lesions (for days, weeks, months and even years). Eventually some children developed neurological sequelae, including epilepsy and cerebral palsy. In this paper it is emphasized that the post-natal development of the grey matter next to these lesions in altered in a specific manner. The post-natal resolution (scarring) of the subpial haemorrhage causes structural changes in the superficial layers of the cortex and permanent leptomeningial heterotopia. The pyramidal cell of layers II and III whose apical dendrites had been partially amputated by haemorrhage became star cells. The grey matter often survived an infarct of the subjacent white matter, since its circulation remained intact. However its post-natal development was altered in a specific way. The post-natal development of this grey matter (partly deprived of sensory information because of the destruction of afferent fibres and with contact lost because on the destruction of efferent fibres) is inevitably different. Projection pyramidal cells (long axon) axotomized by the subjacent lesion, survive the insult and post-natally are changed into intracortical short axon cells. The intrinsic neuropile of the grey matter (partially isolated) increases in an irregular manner which can be seen using immunohistochemical techniques and Golgi's method: areas with a great increase in fibres alternate with areas with few fibres. The presence of large neurones (Golgi's method) with long drendites covered with spines (acquired neuronal hypertrophy) is frequent. In this paper it is suggested that these changes in the grey matter secondary to subpial haemorrhage and hypoxic-ischaemic perinatal infarcts are accompanied by functional changes which may play and important role in the pathogenesis of epilepsy (infantile spasm) and in infantile cerebral palsy.
Adolescent↗
Failure of embryonic hematopoiesis and lethal hemorrhages in mouse embryos heterozygous for a knocked-in leukemia gene CBFB-MYH11.
The fusion oncogene CBFB-MYH11 is generated by a chromosome 16 inversion in human acute myeloid leukemia subtype M4Eo. Mouse embryonic stem (ES) cells heterozygous for this oncogene were generated by inserting part of the human MYH11 cDNA into the mouse Cbfb gene through homologous recombination (knock-in). Chimeric mice were leukemia free, but the ES cells with the knocked-in Cbfb-MYH11 gene did not contribute to their hematopoietic tissues. Mouse embryos heterozygous for Cbfb-MYH11 lacked definitive hematopoiesis and developed multiple fatal hemorrhages around embryonic day 12.5. This phenotype is very similar to that resulting from homozygous deletions of either Cbfb or Cbfa2 (AML1), consistent with a dominant negative function of the Cbfb-MYH11 fusion oncogene. An impairment of primitive hematopoiesis was also observed, however, suggesting a possible additional function of Cbfb-MYH11.
Amino Acid Sequence↗
The CBFbeta subunit is essential for CBFalpha2 (AML1) function in vivo.
The CBFbeta subunit is the non-DNA-binding subunit of the heterodimeric core-binding factor (CBF). CBFbeta associates with DNA-binding CBFalpha subunits and increases their affinity for DNA. Genes encoding the CBFbeta subunit (CBFB) and one of the CBFalpha subunits (CBFA2, otherwise known as AML1) are the most frequent targets of chromosomal translocations in acute leukemias in humans. We and others previously demonstrated that homozygous disruption of the mouse Cbfa2 (AML1) gene results in embryonic lethality at midgestation due to hemorrhaging in the central nervous system and blocks fetal liver hematopoiesis. Here we demonstrate that homozygous mutation of the Cbfb gene results in the same phenotype. Our results demonstrate that the CBFbeta subunit is required for CBFalpha2 function in vivo.
Alleles↗
Developmental neuropathology and impact of perinatal brain damage. I: Hemorrhagic lesions of neocortex.
To establish developmental correlates among perinatal neocortical damage, its impact on the infant developing brain, and its possible role in the pathogenesis of ensuing neurologic sequelae, the neuropathology of acute, subacute (healing), and chronic (repaired) stages of periventricular and layer I (subpial) hemorrhagic lesions have been studied. Thirty-three cases of infants who survived brain damage for hours, days, weeks, months, and/or years and have been studied with the rapid Golgi and other methods. In periventricular hemorrhagic injury: (a) the local destruction of radial glia stop all cellular migration above the lesion; (b) precursor cells already traveling in damaged radial glia also stop their migration, miss their target, and form acquired heterotopias; and, (c) the cytoarchitecture of the overlying and differentiating gray matter may be secondarily altered. In layer I (subpial) hemorrhagic injury: (a) the neocortex external glial limiting membrane is disrupted and must be repaired; (b) its reparation often causes superficial leptomeningeal heterotopias; (c) the cytoarchitecture and intrinsic circuitry of layer I and underlying gray matter are secondarily altered; and, (d) partially damaged (pruning) and/or displaced gray matter neurons undergo post-injury morphologic transformations, atrophy, hypertrophy, and reestablished new "abnormal" connections. These post-injury gray matter cytoarchitectural alterations could eventually play a role in cortical dysfunction and, hence, in the pathogenesis of neurologic sequelae.
Adolescent↗
Prenatal development of fibrous (white matter), protoplasmic (gray matter), and layer I astrocytes in the human cerebral cortex: a Golgi study.
The prenatal developmental histories of layer I, fibrous (white matter), and protoplasmic (gray matter) astrocytes have been studied in the human neocortex by the rapid Golgi method. The developmental route followed by each of these astrocytes is a distinct process which evolves from a specific precursor, occurs at a different time, and is linked to a specific event. The differentiation of layer I astrocytes is linked to the neocortex external glial limiting membrane (EGLM), that of fibrous astrocytes to the early white matter vascularization and maturation, and that of protoplasmic astrocytes to the late gray matter ascending vascularization and maturation. At the start of development, three glial precursors are established in the neocortex: 1) original radial neuroectodermal cells with nuclei above the primordial plexiform layer (PPL) by losing their ependymal and retaining their pial attachments become early astrocytes of layer I and EGLM components; 2) neuroectodermal cells with nuclei below the PPL that retain their pial and ependymal attachments become type I radial glial cells which are committed to the guidance of neurons and the early EGLM maintenance; and, 3) neuroectodermal cells that lose their pial but retain their ependymal attachment are transformed into type II radial glial precursors. By progressively losing their ependymal attachment, type II radial glia precursors become freely migrating cells, establish vascular contacts, and differentiate into fibrous astrocytes (and into oligodendrocytes?) throughout the subplate, developing white matter, and paraventricular regions. After the formation of the gray matter, additional layer I astrocytes are needed for the EGLM late prenatal and postnatal maintenance because type I radial glia cells start to regress and to reabsorb their EGLM endfeet. A late ependyma-to-pia migration of glial precursors progressively repopulates layer I with additional astrocytes and establishes the ephemeral subpial granular layer (SGL) of Ranke. From the 15th week of gestation to the time of birth, late astrocytes of layer I lose their EGLM attachments, migrate freely into the maturing gray matter, establish vascular contacts, and differentiate into protoplasmic astrocytes. The protoplasmic astrocytes of the gray matter evolve from transformation of layer I astrocytes rather than from radial glia cells as is generally believed.
Astrocytes↗
[The development of human cerebral cortex].
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Cerebral Cortex↗
Notochordal alterations in axial skeletal-neural dysraphic disorders.
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Abnormalities, Multiple↗
Ontogenesis of the pyramidal cell of the mammalian neocortex and developmental cytoarchitectonics: a unifying theory.
The prenatal development of the mammalian neocortex has been analyzed, with the rapid Golgi method, in a variety of experimental animals (hamster, mouse, rat, and cat) and in humans. A new developmental conception of the structural organization of the mammalian neocortex is discussed. Neocortical development begins with the establishment of the primordial plexiform layer (PPL) which precedes and is a prerequisite for the subsequent formation of the cortical plate (CP). The formation of the CP occurs, in its entirety, within the PPL. During its development, three fundamental neuronal events occur: migration, early differentiation, and late maturation. All migrating neurons, travelling on radial glial fibers, reach layer I, develop an apical dendrite, and establish contacts with its elements. These newly differentiated neurons assume similar morphology resembling embryonic pyramidal cells. As such, an early differentiation stage common to all neurons of the CP is established. During the late maturation stage, all CP neurons acquire their specific phenotypic structural and functional features. Only pyramidal neurons retain and expand their original connections with layer I while other neuronal types lose these connections. The pyramidal cell is redefined in developmental terms: the neocortex's pyramidal cell is both structurally and functionally locked into position between layer I and the cortical depth of its soma. During mammalian evolution pyramidal cells are forced to structurally and functionally elongate their apical dendrite outwardly to accommodate an increasing amount of information without losing either their original anchorage to layer I or their cortical depth. This unique property of pyramidal neurons is considered to be a mammalian innovation. Based on these observations, a unifying developmental cytoarchitectonic theory applicable to all mammals is proposed. The theory considers the CP to be a mammalian innovation and to represent a single, stratified, and expanding telencephalic nucleus. The theory envisions the mammalian neocortex as an open biological system capable of progressive expansion by the recruitment and transformation of primitive neurons from upper layer II into pyramidal cells. Hence, the number of pyramidal cell strata increases over the course of mammalian phylogeny. The developmental roles of layer I in the migration of neurons, formation of the CP, unique morphology of pyramidal cells, and overall structural organization of the mammalian neocortex are emphasized.
Animals↗