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Diversification of multipotential postmitotic mouse retinal Diversification of multipotential postmitotic mouse retinal ganglion cell precursors into discrete types

ABSTRACT: The genesis of broad neuronal classes from multipotential neural progenitor cells has been extensively studied, but less is known about the diversification of a single neuronal class into multiple types. We used single-cell RNA-seq to study how newly-born (postmitotic) mouse retinal ganglion cell (RGC) precursors diversify into ~45 discrete types. Computational analysis provides evidence that RGC type identity is not specified at mitotic exit, but acquired by gradual, asynchronous fate restriction of postmitotic multipotential precursors. Some types are not identifiable until a week after they are generated. Immature RGCs may be specified to project ipsilaterally or contralaterally to the rest of the brain before their type identity has been determined. Optimal transport inference identifies groups of RGC precursors with largely non-overlapping fates, distinguished by selectively expressed transcription factors that could act as fate determinants. Our study provides a framework for investigating the molecular diversification of discrete types within a neuronal class.

ORGANISM(S): Mus musculus

PROVIDER: GSE185671 | GEO | 2022/02/01

REPOSITORIES: GEO

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Diversification of multipotential postmitotic mouse retinal Diversification of multipotential postmitotic mouse retinal ganglion cell precursors into discrete types

Project description:Diversification of multipotential postmitotic mouse retinal Diversification of multipotential postmitotic mouse retinal ganglion cell precursors into discrete types

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Tbr1 regulates regional and laminar identity of postmitotic neurons in developing neocortex

Project description:Areas and layers of the cerebral cortex are specified by genetic programs that are initiated in progenitor cells and then, implemented in postmitotic neurons. Here, we report that Tbr1, a transcription factor expressed in postmitotic projection neurons, exerts positive and negative control over both regional (areal) and laminar identity. Tbr1 null mice exhibited profound defects of frontal cortex and layer 6 differentiation, as indicated by down-regulation of gene-expression markers such as Bcl6 and Cdh9. Conversely, genes that implement caudal cortex and layer 5 identity, such as Bhlhb5 and Fezf2, were up-regulated in Tbr1 mutants. Tbr1 implements frontal identity in part by direct promoter binding and activation of Auts2, a frontal cortex gene implicated in autism. Tbr1 regulates laminar identity in part by downstream activation or maintenance of Sox5, an important transcription factor controlling neuronal migration and corticofugal axon projections. Similar to Sox5 mutants, Tbr1 mutants exhibit ectopic axon projections to the hypothalamus and cerebral peduncle. Together, our findings show that Tbr1 coordinately regulates regional and laminar identity of postmitotic cortical neurons. Mouse E14.5 neocortices and Postnatal day (P) 0.5 brains: E14.5 neocortices KO, 3; E14.5 neocortices WT, 3; Postnatal day (P) 0.5 brains frontal WT, 4; Postnatal day (P) 0.5 brains frontal KO, 4; Postnatal day (P) 0.5 brains parietal WT, 4; Postnatal day (P) 0.5 brains parietal KO, 4; Postnatal day (P) 0.5 brains occipital WT, 4; Postnatal day (P) 0.5 brains occipital KO, 4.

2010-07-27 | E-GEOD-22371 | biostudies-arrayexpress

Tbr1 regulates regional and laminar identity of postmitotic neurons in developing neocortex

2010-07-27 | GSE22371 | GEO

Sip1 regulates sequential fate decisions through feedback signalling from postmitotic neurons to progenitor cells.

Project description:In the developing cerebral cortex different types of neurons and glial cells are born through a precisely controlled sequence of events. The fate of cortical progenitors, in turn, is determined by an elusive conundrum of temporally and spatially regulated signalling mechanisms. We found the DNA-binding transcription factor Sip1 (also known as Zfhx1b) to be produced at high levels in postmitotic neurons of the cerebral cortex. Conditional deletion of Sip1 in young neocortical neurons was found to induce premature and increased production of upper layer neurons at the expense of deep layer neurons. Furthermore, it caused precocious and increased generation of glial precursors during late corticogenesis, leading subsequently to enhanced astrocytogenesis at early postnatal stages. Expression profiling analysis indicated that the temporal shift in upper layer production coincides with overexpression of the neurotrophin-3 (NT3) gene and altered growth factor signalling in progenitors, while the premature gliogenesis is preceded by upregulation of fibroblast growth factor-9 (Fgf9) gene expression. Chromatin immunoprecipitation and in situ hybridization validates NT3 as a direct target of Sip1 in the cortex and confines the transcriptional repression by Sip1 to postmitotic neurons. Moreover, we show that exogenous application of Fgf9 in solution or via coated beads to wild-type cortical slices induces premature and excessive generation of glial precursors in the germinal zone. In conclusion, our data suggest that throughout corticogenesis Sip1 acts to restrain the level of production of secreted signalling factors in postmitotic neurons. These factors feed back to progenitor cells in order to regulate the timing of cell fate switch and the numbers of neurons and glial cells produced in the developing cerebral cortex.

2009-10-30 | GSE16699 | GEO

Reorganization of postmitotic neuronal chromatin accessibility for maturation of serotonergic identity

Project description:Assembly of transcriptomes encoding unique neuronal identities requires selective accessibility of transcription factors to cis-regulatory sequences in nucleosome-embedded postmitotic chromatin. Yet, the mechanisms controlling postmitotic neuronal chromatin accessibility are poorly understood. Here, we show that unique distal enhancers define the Pet1 neuron lineage that generates serotonin (5-HT) neurons. Heterogeneous single cell chromatin landscapes are established early in postmitotic Pet1 neurons and reveal the putative regulatory programs driving Pet1 neuron subtype identities. Distal enhancer accessibility is highly dynamic as Pet1 neurons mature, suggesting the existence of regulatory factors that reorganize postmitotic neuronal chromatin. We find that Pet1 and Lmx1b control chromatin accessibility to select Pet1-lineage specific enhancers for 5-HT neurotransmission. Additionally, these factors are required to maintain chromatin accessibility during early maturation suggesting that postmitotic neuronal open chromatin is unstable and requires continuous regulatory input. Together our findings reveal postmitotic transcription factors that reorganize accessible chromatin for neuron specialization.

2022-04-14 | GSE185737 | GEO

Evolution of gene expression during an adaptive diversification event

Project description:During a 1,000 generations evolution experiment, two types of bacteria (S and L) repeatedly diverged from a common ancestor (A) in a fully sympatric seasonal environment containing glucose and acetate. We compare the transcription profile of the two derived types and the common ancestor in order to investigate the metabolic modifications associated with this adaptive diversification event. Keywords: time point, experimental evolution

2007-12-15 | GSE8965 | GEO

Comparison of naÃ¯ve, postmitotic (CD44-lo/CD62L-hi) and effector (CD44-hi/CD62L-lo) CD8+ Tcells during BMT in GVHD mice

Project description:NaÃ¯ve CD44-lo/CD62L-hi/CD8+ T cells from C3H.SW mice were compared to CD44-hi/CD82L-lo/CD8+ effector memory T cells and CD44-lo/CD62L-hi/CD8+ postmitotic T cells, using 3 biological replicates of each type of sample. The later two cells types were highly purified at day 14 after transplantation from GVHD B6/SJL mice receiving donor C3H.SW mouse-derived naive CD44-lo/CD62L-hi/CD8+ T cells and T cell-depleted bone marrow. Recipient mice had first been lethally irradiated at a dose of 10Gy in two fractions. This is a MHC-identical minor histocompatibility antigen-mismatched mouse GVHD model of human allogeneic hematopoietic stem cell transplantation. Naive T cell samples were from pools of 2 mice each, while effector memory and postmitotic T cell samples were purified from pools of T cells from 4 mice each. After RNA extraction and cleanup, biotin labeled cRNA was prepared from 600 ng total RNA, using two rounds of in vitro transcription, and hybridized to Affymetrix Mouse Genome 430A 2.0 arrays using standard techniques. Keywords: Cell type comparison 9 samples were analyzed on 9 Affymetrix microarrays to assay mRNA levels. There were 3 biological replicates of each of 3 different cell types.

2010-06-08 | E-GEOD-13743 | biostudies-arrayexpress

Early emergence of cortical interneuron diversity in the mouse embryo

Project description:GABAergic interneurons play crucial roles in the regulation of neural circuit activity in the cerebral cortex. A hallmark of cortical interneurons is their remarkable structural and functional diversity, yet the molecular determinants and the precise timing underlying their diversification remain largely unknown. Here we use single-cell transcriptomics to identify distinct types of progenitor cells and newborn neurons in the ganglionic eminences, the embryonic proliferative regions that give rise to cortical interneurons. These embryonic precursors define temporally and spatially restricted transcriptional trajectories that unambiguously relate to specific classes of interneurons in the adult cerebral cortex. Our findings therefore suggest that interneuron diversity is already patent shortly after neurons become postmitotic through the acquisition of specific transcriptional programs that unfold over several weeks in the developing cortex

2018-03-06 | GSE109796 | GEO

Epithelial Colonization by Gut Dendritic Cells promotes their Functional Diversification

Project description:Dendritic cells (DCs) patrol tissues and transport antigens to lymph nodes to initiate adaptive immune responses. Within tissues, DCs constitute a complex cell population composed of distinct subsets that can exhibit different activation states and functions. How tissue-specific cues orchestrate DC diversification remains elusive. Here, we show that the small intestine included two pools of cDC2s originating from common preDC precursors: (1) lamina propria (LP) CD103+CD11b+ cDC2s that were mature-like pro-inflammatory cells and (2) intraepithelial cDC2s that exhibited an immature-like phenotype as well as tolerogenic properties. These phenotypes resulted from the action of food-derived retinoic acid (ATRA), which enhanced actomyosin contractility and promoted LP cDC2 transmigration into the epithelium. There, cDC2s were imprinted by environmental cues including ATRA itself and the mucus component Muc2. Hence, by reaching distinct sub-tissular niches, DCs can exist as immature and mature cells within the same tissue, revealing an additional mechanism of DC functional diversification.

2021-11-11 | GSE188379 | GEO

p53 binding and gene expression profiles in Drosophila postmitotic and embryonic tissue

Project description:TP53 is the most frequently mutated gene in human cancers, and despite intensive research efforts, genome-scale studies of p53 function in whole animal models are rare. Yet the need for such in vivo studies is underscored by recent challenges to established models indicating that unappreciated p53 functions contribute to tumor suppression. Here we leveraged the Drosophila system to interrogate p53 function in a postmitotic context. In the developing fly, p53 robustly activates important apoptotic genes in response to radiation-induced DNA damage. We have recently shown that a p53 enhancer near the cell death gene reaper (p53RErpr), forms chromatin contacts and enables p53 target activation through long genomic distances. Interestingly, we found that this canonical p53 apoptotic program fails to activate in response to radiation in postmitotic tissue. Furthermore, the lack of apoptotic responses was not associated with altered chromatin contacts; instead we determined that p53 does not occupy the p53RErpr enhancer in postmitotic tissue. In addition, we conducted RNA-seq and ChIP-seq studies to directly compare the developing and postmitotic tissues, and we determined that p53 regulates distinct transcriptional programs in adult heads, which include DNA repair, metabolism and proteolysis genes. Strikingly, in the postmitotic context p53 binding landscapes were poorly correlated with nearby transcriptional effects, raising the possibility that p53 enhancers could be generally acting through long distances.

2019-07-15 | GSE109292 | GEO

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