Cortical White Matter: Beyond the Pale Remarks, Main Conclusions and Discussion

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A distal to proximal gradient of human choroid plexus development, with antagonistic expression of Glut1 and AQP1 in mature cells vs. calbindin and PCNA in proliferative cells

The choroid plexuses (ChP) are highly vascularized tissues suspended from each of the cerebral ventricles. Their main function is to secret CSF that fills the ventricles and the subarachnoid spaces, forming a crucial system for the development and maintenance of the CNS. However, despite the essential role of the ChP–CSF system to regulate the CNS in a global manner, it still remains one of the most understudied areas in neurobiology. Here we define by immunohistochemistry the expression of different proteins involved in the maturation and functionality of the ChP from the late embryological period to maturity. We found an opposite gradient of expression between AQP1 and Glut1 that define functional maturation in the ChP periphery, and PCNA and calbindin, present in the ChP roof zone with proliferative activity. We conclude that the maturation of the ChP matures from distal to proximal, starting in the areas nearest to the cortex, expressing in the distal, mature areas AQP1 and Glut1 (related to ChP functionality to support cortex development), and in the proximal immature areas (ChP root) calbindin and PCNA related to progenitor activity and proliferation

p73 deficiency results in impaired self renewal and premature neuronal differentiation of mouse neural progenitors independently of p53

10 p.-5 fig.The question of how neural progenitor cells maintain its self-renewal throughout life is a fundamental problem in cell biology with implications in cancer, aging and neurodegenerative diseases. In this work, we have analyzed the p73 function in embryonic neural progenitor cell biology using the neurosphere (NS)-assay and showed that p73-loss has a significant role in the maintenance of neurosphere-forming cells in the embryonic brain. A comparative study of NS from Trp73-/-, p53KO, p53KO;Trp73-/-and their wild-type counterparts demonstrated that p73 deficiency results in two independent, but related, phenotypes: a smaller NS size (related to the proliferation and survival of the neural-progenitors) and a decreased capacity to form NS (self-renewal). The former seems to be the result of p53 compensatory activity, whereas the latter is p53 independent. We also demonstrate that p73 deficiency increases the population of neuronal progenitors ready to differentiate into neurons at the expense of depleting the pool of undifferentiated neurosphere-forming cells. Analysis of the neurogenic niches demonstrated that p73-loss depletes the number of neural-progenitor cells, rendering deficient niches in the adult mice. Altogether, our study identifies TP73 as a positive regulator of self-renewal with a role in the maintenance of the neurogenic capacity. Thus, proposing p73 as an important player in the development of neurodegenerative diseases and a potential therapeutic target.This work was supported by Grants SAF2009- 07897 from Spanish Ministerio de Ciencia e Innovacion (to MCM), Grant from Cajas de Ahorro de Castilla y León (to MCM), and Grants LE030A07 (to MMM) and LE015A10-2 (to MCM) from the Junta de Castilla y León.Peer reviewe

p73 deficiency results in impaired self renewal and premature neuronal differentiation of mouse neural progenitors independently of p53

[EN] The question of how neural progenitor cells maintain its self-renewal throughout life is a fundamental problem in cell biology with implications in cancer, aging and neurodegenerative diseases. In this work, we have analyzed the p73 function in embryonic neural progenitor cell biology using the neurosphere (NS)-assay and showed that p73-loss has a significant role in the maintenance of neurosphere-forming cells in the embryonic brain. A comparative study of NS from Trp73-/-, p53KO, p53KO;Trp73-/- and their wild-type counterparts demonstrated that p73 deficiency results in two independent, but related, phenotypes: a smaller NS size (related to the proliferation and survival of the neural-progenitors) and a decreased capacity to form NS (self-renewal). The former seems to be the result of p53 compensatory activity, whereas the latter is p53 independent. We also demonstrate that p73 deficiency increases the population of neuronal progenitors ready to differentiate into neurons at the expense of depleting the pool of undifferentiated neurosphere-forming cells. Analysis of the neurogenic niches demonstrated that p73-loss depletes the number of neural-progenitor cells, rendering deficient niches in the adult mice. Altogether, our study identifies TP73 as a positive regulator of self-renewal with a role in the maintenance of the neurogenic capacity. Thus, proposing p73 as an important player in the development of neurodegenerative diseases and a potential therapeutic targetSILGC is beneficiary of a predoctoral fellowship from Consejo de Educación de la Junta de Castilla y León and RFA from Spanish Ministerio de Ciencia e Innovación. This work was supported by Grants SAF2009-07897 from Spanish Ministerio de Ciencia e Innovacion (to MCM), Grant from Cajas de Ahorro de Castilla y León (to MCM), and Grants LE030A07 (to MMM) and LE015A10-2 (to MCM) from the Junta de Castilla y Leó

A Radial Glia Fascicle Leads Principal Neurons from the Pallial-Subpallial Boundary into the Developing Human Insula

The human insular lobe, in the depth of the Sylvian fissure, displays three main cytoarchitectonic divisions defined by the differentiation of granular layers II and IV. These comprise a rostro-ventral agranular area, an intermediate dysgranular area, and a dorso-caudal granular area. Immunohistochemistry in human embryos and fetuses using antibodies against PCNA, Vimentin, Nestin, Tbr1, and Tb2 reveals that the insular cortex is unique in that it develops far away from the ventricular zone (VZ), with most of its principal neurons deriving from the subventricular zone (SVZ) of the pallial-subpallial boundary (PSB). In human embryos (Carnegie stage 16/17), the rostro-ventral insula is the first cortical region to develop; its Tbr1+ neurons migrate from the PSB along the lateral cortical stream. From 10 gestational weeks (GW) onward, lateral ventricle, ganglionic eminences, and PSB grow forming a C-shaped curvature. The SVZ of the PSB gives rise to a distinct radial glia fiber fascicle (RGF), which courses lateral to the putamen in the external capsule. In the RGF, four components can be established: PF, descending from the prefrontal PSB to the anterior insula; FP, descending from the fronto-parietal PSB toward the intermediate insula; PT, coursing from the PSB near the parieto-temporal junction to the posterior insula, and T, ascending from the temporal PSB and merging with components FP and PT. The RGF fans out at different dorso-ventral and rostro-caudal levels of the insula, with descending fibers predominating over ascending ones. The RGF guides migrating principal neurons toward the future agranular, dysgranular, and granular insular areas, which show an adult-like definition at 32 GW. Despite the narrow subplate, and the absence of an intermediate zone except in the caudal insula, most insular subdivisions develop into a 6-layered isocortex, possibly due to the well developed outer SVZ at the PSB, which is particularly prominent at the level of the dorso-caudal insula. The small size of the initial PSB sector may, however, determine the limited surface expansion of the insula, which is in contrast to the exuberant growth of the opercula deriving from the adjacent frontal-parietal and temporal VZ/SVZ

Feature Article: What is a Cajal-Retzius cell? A reassessment of a classical cell type based on recent observations in the developing neocortex

Supported by grants DGICYT PB94–0582 (G.M.), FRSM 3.4533.95 and ARC 186 (A.M.G.) and DGICYT PB94–0219-CO2–01 (A.F.).Peer reviewe

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

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

Human and monkey fetal brain development of the supramammillary-hippocampal projections: a system involved in the regulation of theta activity.

International audienceThe supramammillary (SUM)-hippocampal pathway plays a central role in the regulation of theta rhythm frequency. We followed its prenatal development in eight Cynomolgus monkeys (Macaca fascicularis) from embryonic day E88 to postnatal day 12 (term 165 days) and in eight human fetuses from 17.5 to 40 gestational weeks, relying on neurochemical criteria established in the adult (Nitsch and Leranth [1993] Neuroscience 55:797-812). We found that 1) SUM afferents reached the dentate juxtagranular and CA2 pyramidal cell layers at midgestation in human fetuses, earlier than in monkeys (two-thirds of gestation [E109]). They co-expressed calretinin, substance P, and acetylcholinesterase but not gamma-aminobutyric acid (GABA) or glutamic acid decarboxylase (GAD); 2) the presumed parent neurons in the monkey SUM expressed calretinin or both calretinin and substance P; 3) most of them were surrounded by GAD-containing terminals that might correspond to the septo-SUM feedback pathway (Leranth et al. [1999] Neuroscience 88:701); and 4) in addition, a large band of calretinin-labeled terminals that did not co-express substance P, GAD, or acetylcholinesterase was present in the deepest one-third of the dentate molecular layer in both the Cynomolgus monkey and human fetuses. It persisted in the adult monkey but not in adult human hippocampus; it remains questionable whether it originates in the SUM. In conclusion, the early ingrowth of the excitatory SUM-hippocampal system in human and non-human primates may contribute to the prenatal activity-dependent development of the hippocampal formation. The possibility and the functional importance of an in utero generation of hippocampal theta-like activity should also be considered

Lhx2 Regulates the Development of the Forebrain Hem System.

International audienceEarly brain development is regulated by the coordinated actions of multiple signaling centers at key boundaries between compartments. Three telencephalic midline structures are in a position to play such roles in forebrain patterning: The cortical hem, the septum, and the thalamic eminence at the diencephalic-telencephalic boundary. These structures express unique complements of signaling molecules, and they also produce distinct populations of Cajal-Retzius cells, which are thought to act as "mobile patterning units," migrating tangentially to cover the telencephalic surface. We show that these 3 structures require the transcription factor Lhx2 to delimit their extent. In the absence of Lhx2 function, all 3 structures are greatly expanded, and the Cajal-Retzius cell population is dramatically increased. We propose that the hem, septum, and thalamic eminence together form a "forebrain hem system" that defines and regulates the formation of the telencephalic midline. Disruptions in the forebrain hem system may be implicated in severe brain malformations such as holoprosencephaly. Lhx2 functions as a central regulator of this system's development. Since all components of the forebrain hem system have been identified across several vertebrate species, the mechanisms that regulate them may have played a fundamental role in driving key aspects of forebrain evolution