279 research outputs found

    Tissue interactions in the developing chick diencephalon

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    This is an open access article distributed under the terms of the Creative Commons Attribution Licens

    Emergence of neuronal diversity from patterning of telencephalic progenitors.

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    During central nervous system (CNS) development, hundreds of distinct neuronal subtypes are generated from a single layer of multipotent neuroepithelial progenitor cells. Within the rostral CNS, initial regionalization of the telencephalon marks the territories where the cerebral cortex and the basal ganglia originate. Subsequent refinement of the primary structures determines the formation of domains of differential gene expression, where distinct fate-restricted progenitors are located. To understand how diversification of neural progenitors and neurons is achieved in the telencephalon, it is important to address early and late patterning events in this context. In particular, important questions include: How does the telencephalon become specified and regionalized along the major spatial axes? Within each region, are the differences in neuronal subtypes established at the progenitor level or at the postmitotic stage? If distinct progenitors exist that are committed to subtype-specific neuronal lineages, how does the diversification emerge? What is the contribution of positional and temporal cues and how is this information integrated into the intrinsic programs of cell identity? WIREs For further resources related to this article, please visit the WIREs website.This work was supported by Medical Research Council (MRC) grants G0700758 and MR/K018329/1 and Doctoral Training Award (LH); RA is supported by an MRC postdoctoral fellowship.This is the accepted manuscript. The final version is available from Wiley at http://onlinelibrary.wiley.com/doi/10.1002/wdev.174/abstract

    Absence of Nodal signaling promotes precocious neural differentiation in the mouse embryo

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    AbstractAfter implantation, mouse embryos deficient for the activity of the transforming growth factor-β member Nodal fail to form both the mesoderm and the definitive endoderm. They also fail to specify the anterior visceral endoderm, a specialized signaling center which has been shown to be required for the establishment of anterior identity in the epiblast. Our study reveals that Nodal−/− epiblast cells nevertheless express prematurely and ectopically molecular markers specific of anterior fate. Our analysis shows that neural specification occurs and regional identities characteristic of the forebrain are established precociously in the Nodal−/− mutant with a sequential progression equivalent to that of wild-type embryo. When explanted and cultured in vitro, Nodal−/− epiblast cells readily differentiate into neurons. Genes normally transcribed in organizer-derived tissues, such as Gsc and Foxa2, are also expressed in Nodal−/− epiblast. The analysis of Nodal−/−;Gsc−/− compound mutant embryos shows that Gsc activity plays no critical role in the acquisition of forebrain characters by Nodal-deficient cells. This study suggests that the initial steps of neural specification and forebrain development may take place well before gastrulation in the mouse and highlights a possible role for Nodal, at pregastrula stages, in the inhibition of anterior and neural fate determination

    Foxg1 control of neuronal morphology

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    The architecture of neocortical projection neurons is subject of a complex gene control. Here we demonstrated that Foxg1, a transcription factor gene which patterns the early rostral brain and sets the pace of telencephalic neuronogenesis, specifically stimulates dendrite elongation. This phenomenon occurs in vivo like in vitro, and it is detectable even upon moderate changes of Foxg1 expression levels. We found that Foxg1 acts by (a) stimulating Hes1, which in turn upregulates the well-known prodendritogenic effector pCreb1, and (b) downregulating Syt and Ndr1, namely two established antagonizers of dendrite elongation. Foxg1 impact on Hes1 turned out to stem from direct transactivation and indirect derepression. The latter was mediated by knock-down of Nfia and Sirt1, which normally antagonize Hes1 transcription. Next, Foxg1-driven pCreb1 upregulation required PKA and AKT, and correlated with reduced PP1 and PP2A phosphatase activity. Finally, Foxg1/Hes1 circuitry mastering dendritogenesis included two key homeostatic branches, i.e. Hes1-dependent Foxg1 downregulation and Syt upregulation. These findings contribute to clarify normal neurodevelopmental and activityrelated regulation of neuritogenesis. They further suggest that an abnormal sizing of the dendritic tree of neocortical projection neurons may occur in West and Rett syndrome patients with anomalous FOXG1 allele dosages and contribute to their neuropathological profiles

    Foxa4 favours notochord formation by inhibiting contiguous mesodermal fates and restricts anterior neural development in Xenopus embryos

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    In vertebrates, the embryonic dorsal midline is a crucial signalling centre that patterns the surrounding tissues during development. Members of the FoxA subfamily of transcription factors are expressed in the structures that compose this centre. Foxa2 is essential for dorsal midline development in mammals, since knock-out mouse embryos lack a definitive node, notochord and floor plate. The related gene foxA4 is only present in amphibians. Expression begins in the blastula –chordin and –noggin expressing centre (BCNE) and is later restricted to the dorsal midline derivatives of the Spemann's organiser. It was suggested that the early functions of mammalian foxa2 are carried out by foxA4 in frogs, but functional experiments were needed to test this hypothesis. Here, we show that some important dorsal midline functions of mammalian foxa2 are exerted by foxA4 in Xenopus. We provide new evidence that the latter prevents the respecification of dorsal midline precursors towards contiguous fates, inhibiting prechordal and paraxial mesoderm development in favour of the notochord. In addition, we show that foxA4 is required for the correct regionalisation and maintenance of the central nervous system. FoxA4 participates in constraining the prospective rostral forebrain territory during neural specification and is necessary for the correct segregation of the most anterior ectodermal derivatives, such as the cement gland and the pituitary anlagen. Moreover, the early expression of foxA4 in the BCNE (which contains precursors of the whole forebrain and most of the midbrain and hindbrain) is directly required to restrict anterior neural development.Fil: Murgan, Sabrina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Castro Colabianchi, Aitana Manuela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Monti, Renato José. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Boyadjián López, Laura Elena. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencias; ArgentinaFil: Aguirre, Cecilia Elena. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Gonzalez Stivala, Ernesto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Carrasco, Andres Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Lopez, Silvia Liliana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; Argentin

    The Prethalamus Is Established during Gastrulation and Influences Diencephalic Regionalization

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    The vertebrate neural plate contains distinct domains of gene expression, prefiguring the future brain areas. In this study, we draw an extended expression map of the rostral neural plate that reveals discrete domains inside the presumptive posterior forebrain. We show, by fate mapping, that these well-defined cell populations will develop into specific diencephalic regions. To address whether these early subterritories are already committed to restricted identities, we began to analyse the consequences of ablation and transplantation of these specific cell populations. We found that precursors of the prethalamus are already specified and irreplaceable at late gastrula stage, because ablation of these cells results in loss of prethalamic markers. Moreover, when transplanted into the ectopic environment of the presumptive hindbrain, these cells still pursue their prethalamic differentiation program. Finally, transplantation of these precursors, in the rostral-most neural epithelium, induces changes in cell identity in the surrounding host forebrain. This cell–non-autonomous property led us to propose that these committed prethalamic precursors may play an instructive role in the regionalization of the developing diencephalon

    Brain diversity develops early: a study on the role of patterning on vertebrate brain evolution

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    The brain has been one of the central foci in studies of vertebrate evolution. Work in East African cichlids and other emerging fish models like the Mexican cavefish (Astyanax mexicanus) offer new insight on the role of patterning on brain evolution. These fish can be grouped into two major categories according to habitat; for cichlids it is rock-dwelling (known locally as mbuna) and sand-dwelling (non-mbuna) lineage. The brain development of mbuna versus non-mbuna is defined by changes in gene deployment working along the dorsal/ventral (DV) and anterior/posterior (AP) neuraxes, respectively. Comparison of disparate fish ecotypes offer a new perspective of the role of patterning on brain evolution; through the slight and early modification of signal pathways working across 3-D axes, and a subsequent magnifying effect across ontogeny, evolution can generate widespread changes in the brain. To illustrate this patterning model of brain evolution, two comparative studies were done between mbuna and non-mbuna, examining the action of gene pathways that work to pattern the cichlid forebrain. The first study found that non-mbuna cichlids have a more rapid AP expansion of a gene pathway (Wingless) into the presumptive midbrain and diencephalon versus mbuna. These forebrain structures are involved in sight processing and could be of ecological benefit to vision-focused non-mbuna. The second study described a difference within the developing telencephalon. The embryonic telencephalon is split into the pallium, which processes visual signals, and the subpallium, which develops into the olfactory bulbs. Mbuna possess a larger subpallium relative to non-mbuna, which have a larger pallium. This was correlated to a more rapid expansion of another gene pathway (Hedgehog) along the DV axis. The difference in size of the pallial vs. subpallialial comparments between cichlids can be correlated to expanded olfaction in mbuna and vision in non-mbuna adult brains. Overall, East African cichlids are an excellent system to investigate the role of patterning on brain evolution because they allow for the comparison of the earliest patterning events in brain ontogeny between distinct ecotypes. These fish systems link study in brain development to the brain morphology comparisons employed in classic studies of brain evolution.PhDCommittee Chair: Streelman, Jeffery Todd; Committee Member: Condie, Brian; Committee Member: Goodisman, Michael; Committee Member: Hay, Mark; Committee Member: Yi, Sooji

    Role of Apc in cortical development

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    Cerebral cortex development is a complicated process which is not completely understood. There are a lot of signaling interactions during morphogenesis of the cortex. One of the signaling pathways is Wnt. Adenomatous polyposis coli (Apc) is a key regulator of the canonical Wnt pathway. Also Ape is important to transducer signals from the planar cell polarity (PCP) Wnt pathway. This thesis is devoted to the role of Ape protein in the development of the mouse dorsal telencephalon. Apc⁻/⁻ embryos die at gastrulation, therefore Emxlᶜʳᵉ conditional knock-out approach was used to overcome this problem. Cre expression driven by Emxl promoter allows knock-out Apc in the cortex. Current work presents description and possible explanations of Apc functions in the developing cerebral cortex.Conditional knock-out of Apc in the cortex using Emxlᶜʳᵉ leads to severe developmental defects in this region. This shows that Apc is required for normal development of the cerebral cortex. The earliest found defect is nuclear translocation of beta-catenin which is demonstrating that Apc is important to regulate translocation of beta-catenin to the nucleus. This finding supports results of other researchers. This abnormality was found at embryonic day 10.5 (El0.5), which shows that Apc has a controlling function from the beginning of cortical development. Later in development nuclear beta-catenin accumulation becomes more pronounced. Experiments with BatGal reporter mice show that stabilized beta-catenin is able to stimulate the canonical Wnt pathway. Wnt target genes (C-myc, Cyclin Dl) are activated also. However Axin 2 expression is highly up-regulated which reflects negative feedback to the canonical Wnt signaling activation. Polarity of cells is lost from El2.5, which suggests that the cytoskeletal functions of Ape are affected by Ape deletion. Adhesion defect and defect in neuronal processes elongation provide additional evidence of the cytoskeleton disregulation. Therefore, the deletion of Apc leads to over-activation of the canonical Wnt pathway and disregulation of cytoskeleton functioning.Identity of the dorsal telencephalon is unclear in conditional Ape mutant embryos. Expression of Foxgl shows that the mutant dorsal telencephalon loses telencephalic identity from El2.5. There are signs that the mutant dorsal telencephalon expresses markers (Pax3, Wntl) of more caudal regions of the brain. However markers normally expressed in the cerebral cortex (Pax6, Tbr1) are still present. Pax6 is downregulated in the mutant but there are no signs that the pallial subpal 1 ial boundary is compromised. Apical progenitor population is decreased. Decreased Tbr2 expression shows that intermediate progenitor pool is reduced also. Medial regions of the mutant dorsal telencephalon are more affected than lateral possibly due to a gradient in Emxl expression in the cortex. My data show that Ape is important for proper patterning of the cortex probably mostly by antagonizing the canonical Wnt pathway. However a precise mechanism is yet to be elucidated.Cell-cycle investigation revealed that in the absence of Apc, S-phase and cell cycle length remains more or less similar to the control. However the proliferative pool is decreased and most cells of the mutant are blocked in G1 phase. This defect progresses with the age. Aneuploidy was not detected in the mutant cells. The G1 blockade is related to p21 up-regulation. Also apoptosis is increased in the mutant but level of p53 is not changed. My data suggests that apoptosis and p21 expression is stimulated by Wtl expression, which reflects tumour suppression. Thus, Ape deletion leads to defects in maintenance of the size of progenitor pool and regulation of apoptosis
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