Podcasts about tbr2

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.06.17.153551v1?rss=1 Authors: Mao, C.-A., Chen, C.-K., Kiyama, T., Weber, N., Whitaker, C. M., Pan, P., Badea, T. C., Massey, S. C. Abstract: The mammalian retina contains more than 40 retinal ganglion cell (RGC) subtypes based on their unique morphologies, functions, and molecular profiles. Among them, intrinsically photosensitive RGCs (ipRGCs) are the first specified RGC type that emerged from a common pool of retinal progenitor cells. Previous work has shown that T-box transcription factor T-brain 2 (Tbr2) is essential for the formation and maintenance of ipRGCs, and Tbr2-expressing RGCs activate Opn4 expression upon native ipRGC loss, suggesting that Tbr2+ RGCs can serve as a reservoir for ipRGCs. However, the identity of Tbr2+ RGCs has not been fully vetted, and the developmental and molecular mechanisms underlying the formation of native and reservoir ipRGCs remain unclear. Here, we showed that Tbr2-expressing retinal neurons include RGCs and GABAergic displaced amacrine cells (dACs). Using genetic sparse labeling, we demonstrated that the majority of Tbr2+ RGCs are intrinsically photosensitive and morphologically indistinguishable from known ipRGC types and have identical retinofugal projections. Additionally, we found a minor fraction of Pou4f1-expressing Tbr2+ RGCs marks a unique OFF RGC subtype. Most of the Tbr2+ RGCs can be ablated by anti-melanopsin-SAP toxin in adult retinas, supporting that Tbr2+ RGCs contain reservoir ipRGCs that express melanopsin at varying levels. When Tbr2 is deleted in adult retinas, Opn4 expression is diminished followed by the death of Tbr2-deficient cells, suggesting that Tbr2 is essential for both Opn4 expression and ipRGC survival. Finally, Tbr2 extensively occupies multiple T-elements in the Opn4 locus, indicating a direct regulatory role for Tbr2 on Opn4 transcription. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.05.08.084129v1?rss=1 Authors: Veerasammy, S., Van Steenwinckel, J., Le-Charpentier, T., Seo, J. H., Fleiss, B., Gressens, P., Levison, S. W. Abstract: Meta-analyses have revealed associations between the incidence of maternal infections during pregnancy, premature birth, smaller brain volumes, and subsequent cognitive, motor and behavioral deficits as these children mature. Inflammation during pregnancy in rodents produces cognitive and behavioral deficits in the offspring that are similar to those reported in human studies. These deficits are accompanied by decreased neurogenesis and proliferation in the subgranular zone (SGZ) of the dentate gyrus (DG) of the hippocampus. As systemically administering interleukin-1{beta} (IL-1{beta}) to neonatal mice recapitulates many of the brain abnormalities seen in premature babies including developmental delays, the goal of this study was to determine whether IL-1-mediated neuroinflammation would affect hippocampal growth during development to produce cognitive and behavioral abnormalities. For these studies, 10 ng/g IL-1{beta} was administered twice daily to Swiss Webster mice during the first 5 days of life, which increased hippocampal levels of IL-1 and acutely reduced the proliferation of Tbr2+ neural progenitors in the DG. In vitro , both IL-1 and IL-1{beta} produced G1/S cell cycle arrest that resulted in reduced progenitor cell proliferation within the transit amplifying progenitor cell cohort. By contrast, IL-1{beta} treatment increased neural stem cell frequency. Upon terminating IL-1{beta} treatment, the progenitor cell pool regained its proliferative capacity. An earlier study that used this in vivo model of perinatal inflammation showed that mice that received IL-1{beta} as neonates displayed memory deficits which suggested abnormal hippocampal function. To evaluate whether other cognitive and behavioral traits associated with hippocampal function would also be altered, mice were tested in tasks designed to assess exploratory and anxiety behavior as well as working and spatial memory. Interestingly, mice that received IL-1{beta} as neonates showed signs of anxiety in several behavioral assays during adolescence that were also evident in adulthood. Additionally, these mice did not display working memory deficits in adulthood, but they did display deficits in long-term spatial memory. Altogether, these data support the view that perinatal inflammation negatively affects the developing hippocampus producing behavioral deficits that persist into adulthood. These data provide a new perspective into the origin of the cognitive and behavioral impairments observed in prematurely-born sick infants. Copy rights belong to original authors. Visit the link for more info

Insights into the developmental processes during which the brain forms from the neuroepithelium may provide a deeper understanding how the brain works. The Rho family of small GTPases is known for its many cell biological functions such as regulation of the cytoskeleton, gene expression, cell migration, adhesion, cell polarity and the cell cycle. All of these functions are of importance during the formation of the cerebral neocortex, which consists of the generation of its different cell types, their migration to their destination and their maturation to a functional network. These roles have been mostly established in vitro using dominant negative or constitutively active constructs. Since these approaches are often not entirely specific for single pathways, this work used the Cre/loxP system to genetically delete an individual member of the Rho family, RhoA, to examine its role following a loss-of-function approach. Specifically, we examined a mouse line where part of the RhoA gene has been deleted by means of the Emx1::Cre mouse line. This idea is based on previous experiences with the deletion of Cdc42 in the developing neocortex, which leads to a loss of apical progenitors. RhoA often works as a functional antagonist to Cdc42. Using immunofluorescence, we could detect a loss of RhoA at embryonic day 12 (E12) in Emx1::Cre-positive offspring carrying the floxed RhoA-construct in both alleles (cKO). At E14, we detected an increase in mitotic cells to 160% (±25%, p

Background: While the diversity and spatio-temporal origin of olfactory bulb (OB) GABAergic interneurons has been studied in detail, much less is known about the subtypes of glutamatergic OB interneurons. Results: We studied the temporal generation and diversity of Neurog2-positive precursor progeny using an inducible genetic fate mapping approach. We show that all subtypes of glutamatergic neurons derive from Neurog2 positive progenitors during development of the OB. Projection neurons, that is, mitral and tufted cells, are produced at early embryonic stages, while a heterogeneous population of glutamatergic juxtaglomerular neurons are generated at later embryonic as well as at perinatal stages. While most juxtaglomerular neurons express the T-Box protein Tbr2, those generated later also express Tbr1. Based on morphological features, these juxtaglomerular cells can be identified as tufted interneurons and short axon cells, respectively. Finally, targeted electroporation experiments provide evidence that while the majority of OB glutamatergic neurons are generated from intrabulbar progenitors, a small portion of them originate from extrabulbar regions at perinatal ages. Conclusions: We provide the first comprehensive analysis of the temporal and spatial generation of OB glutamatergic neurons and identify distinct populations of juxtaglomerular interneurons that differ in their antigenic properties and time of origin.

The vast majority of neurons in the murine brain are generated during embryonic neurogenesis. However, at least two neurogenic niches continue to produce specific types of neurons throughout life. The adult dentate gyrus harbours stem cells that generate dentate granule neurons and the subependymal zone produces distinct types of olfactory interneurons. The adult neurogenic subependymal zone is derived from the embryonic dorsal and ventral subventricular zone of the telencephalon, i. e. progenitor domains which generate both the ventral and dorsal glutamatergic and GABAergic neurons, respectively. While a cascade of transcription factors beginning with Pax6 governs the generation of glutamatergic cortical neurons, transcription factors of the Dlx family are crucial for the embryonic neurogenesis of GABAergic neurons. Notably, Pax6 and Dlx transcription factors factors are expressed in the adult subependymal zone. In this study I investigated the regionalization of the adult subependymal neurogenic niche in regard to Pax6 and Dlx and I examined the role of these factors in neuronal subtype specification. Consistent with their embryonic origin progenitors in the adult brain express Dlx1 and Dlx2 in the lateral, but not the dorsal subependymal zone. Using retroviral vectors I demonstrated that Dlx2 is necessary for neurogenesis of virtually all olfactory interneurons arising from the lateral subependymal zone. Beyond its function in generic neurogenesis, Dlx2 plays a crucial role in neuronal subtype specification in the adult olfactory bulb promoting specification of dopaminergic interneurons. Strikingly, Dlx2 requires interaction with Pax6, as Pax6 deletion blocks Dlx2 mediated neuronal specification. Of note, however, Pax6 protein is expressed in a gradient being especially abundant in dorsal regions of the adult subpenedymal zone. While playing obviously a role in the genesis of GABAergic interneurons, I also investigated whether the dorsal subependymal zone could give rise to glutamatergic neurons which have so far been overlooked. Surprisingly, progenitors located mainly in dorso-rostral regions of the subependymal zone express transcription factors previously linked to glutamatergic neurogenesis like Pax6 → Neurogenin2 → Tbr2 → Tbr1. These neurons migrate along the rostral migratory stream and integrate into the glomerular layer of the olfactory bulb. Finally, I provide evidence that these Tbr2-positive cells could become recruited following cortical lesions where callosal projection neurons are depleted.

Radial glial cells are a widespread non-neuronal cell type in the developing central nervous system (CNS) of all vertebrates. In the cortex, distinct subsets of radial glial cells coexist that are either multipotent or specified towards the generation of neurons or glial cells (Malatesta et al., 2000). Radial glial cells in the cerebral cortex are also the source of a second type of neurogenic progenitors, called basal progenitors. However, whether the generation of basal progenitors occurs in a stochastic manner or whether a specific lineage of radial glial cells is specified towards the generation of these progenitors has not been previously known. To identify functionally distinct lineages of cortical radial glial cells, I developed a new strategy using fluorescence-activated cell sorting (FACS) to isolate them and study their progeny. I isolated radial glial cells by FACS from a transgenic mouse line in which green fluorescent protein (GFP) expression is under the control of the human GFAP promoter. Strikingly, GFP intensity was correlated with cell fate. Selective enrichment of cells with a higher GFP intensity separated a largely non-neurogenic from a neurogenic (low GFP-intensity) subsets of radial glial cells. Notable differences on the progeny of these distinct sets of radial glia were found. The neurogenic radial glial cells subset generated neurons directly and those that are largely non-neurogenic also gave rise to a small proportion of Tbr2-positive basal progenitors that are then neurogenic. Thus, this last subset comprises an indirect neurogenic population of radial glial cells present in the developing cortex. Microarray analysis of these distinct sets of radial glial cells revealed profound differences in their gene expression. Genes related to gliogenesis, proliferation and cell-cycle regulation were expressed at higher levels in the largely non-neurogenic set of radial glia while genes related to neurogenesis, cell adhesion, neurotransmitter secretion and axon guidance were expressed mostly in the neurogenic subset. Moreover, the set of genes expressed at higher levels in the neurogenic radial glia was down-regulated at later stages (cortical radial glia at E18). Thus, this analysis reveals differences at the transcriptional level between direct neurogenic and largely non-neurogenic radial glial cells, supporting their intrinsic lineage differences. The functional analysis of a key fate determinant for neurogenesis from radial glia discovered in this transcriptome analysis will also be presented. This gene is the transcription factor AP2γ which was expressed at significantly higher levels in radial glial cells generating basal progenitors. AP2γ is restricted to the ventricular zone (VZ)/subventricular zone (SVZ) regions of the developing cerebral cortex in the entire nervous system and is also highly expressed in primate and human cortical progenitors. Its genetic deletion within the mouse cerebral cortex results in the molecular misspecification of basal progenitors with decreased levels of Tbr2 and Math3 expression, as well as their overproliferation associated with increased cell death specifically in the occipital cortex. This causes a reduction in upper layer neuron generation with intriguing functional defects in visual acuity. Gain-of-function studies also revealed the important role of AP2γ for the adequate specification and development of basal progenitors in the cerebral cortex, while apical progenitors were not affected by the loss- and gain-of-function of this transcription factor. Thus, I show for the first time the prospective isolation of distinct radial glia subtypes in the mouse developing cortex demonstrated at the molecular and functional level.