Cellular basis of pineal gland development: Emerging role of microglia as phenotype regulator

The adult pineal gland is composed of pinealocytes, astrocytes, microglia, and other interstitial cells that have been described in detail. However, factors that contribute to pineal development have not been fully elucidated, nor have pineal cell lineages been well characterized. We applied systematic double, triple and quadruple labeling of cell-specific markers on prenatal, postnatal and mature rat pineal gland tissue combined with confocal microscopy to provide a comprehensive view of the cellular dynamics and cell lineages that contribute to pineal gland development. The pineal gland begins as an evagination of neuroepithelium in the roof of the third ventricle. The pineal primordium initially consists of radially aligned Pax6+ precursor cells that express vimentin and divide at the ventricular lumen. After the tubular neuroepithelium fuses, the distribution of Pax6+ cells transitions to include rosette-like structures and later, dispersed cells. In the developing gland all dividing cells express Pax6, indicating that Pax6+ precursor cells generate pinealocytes and some interstitial cells. The density of Pax6+ cells decreases across pineal development as a result of cellular differentiation and microglial phagocytosis, but Pax6+ cells remain in the adult gland as a distinct population. Microglial colonization begins after pineal recess formation. Microglial phagocytosis of Pax6+ cells is not common at early stages but increases as microglia colonize the gland. In the postnatal gland microglia affiliate with Tuj1+ nerve fibers, IB4+ blood vessels, and Pax6+ cells. We demonstrate that microglia engulf Pax6+ cells, nerve fibers, and blood vessel-related elements, but not pinealocytes. We conclude that microglia play a role in pineal gland formation and homeostasis by regulating the precursor cell population, remodeling blood vessels and pruning sympathetic nerve fibers.Fil: Ibañez Rodriguez, María Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Noctor, Stephen C.. University of California; Estados UnidosFil: Muñoz, Estela Maris. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentin

Abnormal white matter tracts resembling pencil fibers involving prefrontal cortex (Brodmann area 47) in autism: a case report.

BackgroundAutism is not correlated with any neuropathological hallmark as the brain of autistic individuals lack defined lesions. However, previous investigations have reported cortical heterotopias and local distortion of the cytoarchitecture of the neocortex in some cases of autism.Case presentationOur patient was a 40-year-old white woman diagnosed at an early age with autism and mental retardation. Pencil fibers were present within the prefrontal cortex (Brodmann area 47) and its composition resembled that of the underlying white matter region. Pencil fibers encompassed most of the extent of the cortical grey matter and were populated by oligodendrocytes, astrocytes, and microglial cells, but not by neurons.ConclusionsHere we report a new cytoarchitectural abnormality that has not been previously described in autism. Future pathological examinations should keep in mind the potential presence of pencil fibers within the prefrontal cortex of cases with autism

Microglia enhances proliferation of neural progenitor cells in an in vitro model of hypoxic-ischemic injury

Microglial cells are the primary immune cells in the central nervous system. In the mature brain, microglia perform functions that include eliminating pathogens and clearing dead/dying cells and cellular debris through phagocytosis. In the immature brain, microglia perform functions that include synapse development and the regulation of cell production through extensive contact with and phagocytosis of neural progenitor cells (NPCs). However, the functional role of microglia in the proliferation and differentiation of NPCs under hypoxic-ischemic (HI) injury is not clear. Here, we tested the hypothesis that microglia enhance NPCs proliferation following HI insult. Primary NPCs cultures were divided into four treatment groups: 1) normoxic NPCs (NN); 2) normoxic NPCs cocultured with microglia (NN+M); 3) hypoxic NPCs (HN); and 4) hypoxic NPCs cocultured with microglia (HN+M). Hypoxic-ischemic injury was induced by pretreatment of the cell cultures with 100 µM deferoxamine mesylate (DFO). NPCs treated with 100 µM DFO (HN groups) for 24 hours had significantly increased expression of hypoxia-inducible factor 1 alpha (HIF-1α), a marker of hypoxic cells. Cell number, protein expression, mitosis, and cell cycle phase were examined, and the data were compared between the four groups. We found that the number of cells expressing the NPCs marker Sox2 increased significantly in the HN+M group and that the number of PH3-positive cells increased in the HN+M group; flow cytometry analysis showed a significant increase in the percentage of cells in the G2/M phase in the HN+M group. In summary, these results support the concept that microglia enhance the survival of NPCs under HI injury by increasing NPCs proliferation, survival, and differentiation. These results further suggest that microglia may induce neuroprotective effects after hypoxic injury that can be explored to develop novel therapeutic strategies for the treatment of HI injury in the immature brain

Neural Progenitor Cell Terminology

Since descriptions of neural precursor cells (NPCs) were published in the late 19th century, neuroanatomists have used a variety of terms to describe these cells, each term reflecting contemporary understanding of cellular characteristics and function. As the field gained knowledge through a combination of technical advance and individual insight, the terminology describing NPCs changed to incorporate new information. While there is a trend toward consensus and streamlining of terminology over time, to this day scientists use different terms for NPCs that reflect their field and perspective, i.e., terms arising from molecular, cellular, or anatomical sciences. Here we review past and current terminology used to refer to NPCs, including embryonic and adult precursor cells of the cerebral cortex and hippocampus

Cajal, Retzius, and Cajal–Retzius cells

The marginal zone (MZ) of the prenatal cerebral cortex plays a crucial role in cellular migration and laminar patterning in the developing neocortex and its equivalent in the adult brain - layer I, participates in cortical circuitry integration within the adult neocortex. The MZ/layer I, which has also been called the plexiform layer and cell-poor zone of Meynert, among others, is home to several cell populations including glia, neurons and Cajal-Retzius (CR) cells. Cajal once said that the MZ is one of the oldest formations in the phylogenetic series, and that the characteristics of layer I in human are similar in all vertebrates except fish (Ramon y Cajal, 1899). Despite the presence of CR cells in the MZ/layer I of all developing and adult vertebrate brains, and more than one hundred years of research, the phenotype and function of layer I cells have still not been clearly defined. Recent technological advances have yielded significant progress in functional and developmental studies, but much remains to be understood about neurons in MZ/layer I. Since the time of Retzius and Cajal, and continuing with modern era research from the likes of Marín-Padilla, the study of CR cells has been based on their morphological characteristics in Golgi staining. However, since Cajal’s initial description, the term ‘CR cell’ has been applied differently and now is often used to indicate reelin (Reln) positive cells in MZ/layer I. Here we review the history of work by Cajal, Retzius and others pertaining to CR cells. We will establish a link between original descriptions of CR cell morphology by Cajal, Retzius and others, and current understandings of the cell populations that reside in MZ/layer I based on the use of cellular markers. We propose to use the term ‘CR cell’ for the class of neurons that express Reln in the MZ/layer I in both prenatal, developing and adult cerebral cortex

Radial glia in the proliferative ventricular zone of the embryonic and adult turtle, Trachemys scripta elegans.

To better understand the role of radial glial (RG) cells in the evolution of the mammalian cerebral cortex, we investigated the role of RG cells in the dorsal cortex and dorsal ventricular ridge of the turtle, Trachemys scripta elegans. Unlike mammals, the glial architecture of adult reptile consists mainly of ependymoradial glia, which share features with mammalian RG cells, and which may contribute to neurogenesis that continues throughout the lifespan of the turtle. To evaluate the morphology and proliferative capacity of ependymoradial glia (here referred to as RG cells) in the dorsal cortex of embryonic and adult turtle, we adapted the cortical electroporation technique, commonly used in rodents, to the turtle telencephalon. Here, we demonstrate the morphological and functional characteristics of RG cells in the developing turtle dorsal cortex. We show that cell division occurs both at the ventricle and away from the ventricle, that RG cells undergo division at the ventricle during neurogenic stages of development, and that mitotic Tbr2+ precursor cells, a hallmark of the mammalian SVZ, are present in the turtle cortex. In the adult turtle, we show that RG cells encompass a morphologically heterogeneous population, particularly in the subpallium where proliferation is most prevalent. One RG subtype is similar to RG cells in the developing mammalian cortex, while 2 other RG subtypes appear to be distinct from those seen in mammal. We propose that the different subtypes of RG cells in the adult turtle perform distinct functions

Comparative Analysis of the Subventricular Zone in Rat, Ferret and Macaque: Evidence for an Outer Subventricular Zone in Rodents

The mammalian cerebral cortex arises from precursor cells that reside in a proliferative region surrounding the lateral ventricles of the developing brain. Recent work has shown that precursor cells in the subventricular zone (SVZ) provide a major contribution to prenatal cortical neurogenesis, and that the SVZ is significantly thicker in gyrencephalic mammals such as primates than it is in lissencephalic mammals including rodents. Identifying characteristics that are shared by or that distinguish cortical precursor cells across mammalian species will shed light on factors that regulate cortical neurogenesis and may point toward mechanisms that underlie the evolutionary expansion of the neocortex in gyrencephalic mammals. We immunostained sections of the developing cerebral cortex from lissencephalic rats, and from gyrencephalic ferrets and macaques to compare the distribution of precursor cell types in each species. We also performed time-lapse imaging of precursor cells in the developing rat neocortex. We show that the distribution of Pax6+ and Tbr2+ precursor cells is similar in lissencephalic rat and gyrencephalic ferret, and different in the gyrencephalic cortex of macaque. We show that mitotic Pax6+ translocating radial glial cells (tRG) are present in the cerebral cortex of each species during and after neurogenesis, demonstrating that the function of Pax6+ tRG cells is not restricted to neurogenesis. Furthermore, we show that Olig2 expression distinguishes two distinct subtypes of Pax6+ tRG cells. Finally we present a novel method for discriminating the inner and outer SVZ across mammalian species and show that the key cytoarchitectural features and cell types that define the outer SVZ in developing primates are present in the developing rat neocortex. Our data demonstrate that the developing rat cerebral cortex possesses an outer subventricular zone during late stages of cortical neurogenesis and that the developing rodent cortex shares important features with that of primates