Zebrafish Rfx4 controls dorsal and ventral midline formation in the neural tube
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ABSTRACT:
ORGANISM(S): Danio rerio
PROVIDER: GSE101390 | GEO | 2018/02/27
REPOSITORIES: GEO
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Project description:BACKGROUND:Rfx winged-helix transcription factors, best known as key regulators of core ciliogenesis, also play ciliogenesis-independent roles during neural development. Mammalian Rfx4 controls neural tube morphogenesis via both mechanisms. RESULTS:We set out to identify conserved aspects of rfx4 gene function during vertebrate development and to establish a new genetic model in which to analyze these mechanisms further. To this end, we have generated frame-shift alleles in the zebrafish rfx4 locus using CRISPR/Cas9 mutagenesis. Using RNAseq-based transcriptome analysis, in situ hybridization and immunostaining we identified a requirement for zebrafish rfx4 in the forming midlines of the caudal neural tube. These functions are mediated, least in part, through transcriptional regulation of several zic genes in the dorsal hindbrain and of foxa2 in the ventral hindbrain and spinal cord (floor plate). CONCLUSIONS:The midline patterning functions of rfx4 are conserved, because rfx4 regulates transcription of foxa2 and zic2 in zebrafish and in mouse. In contrast, zebrafish rfx4 function is dispensable for forebrain morphogenesis, while mouse rfx4 is required for normal formation of forebrain ventricles in a ciliogenesis-dependent manner. Collectively, this report identifies conserved aspects of rfx4 function and establishes a robust new genetic model for in-depth dissection of these mechanisms. Developmental Dynamics 247:650-659, 2018. © 2017 Wiley Periodicals, Inc.
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Project description:Dorsal neural tube-derived retinoic acid promotes the end of neural crest production and transition into a definitive roof plate. Here we analyze how this impacts the segregation of central and peripheral lineages, a process essential for tissue patterning and function. Localized in-ovo inhibition of retinoic acid activity followed by single cell transcriptomics unraveled a comprehensive list of differentially expressed genes relevant to these processes. Importantly, progenitors co-expressed neural crest, roof plate and di1 interneuron markers indicating a failure in proper lineage segregation. Furthermore, we found that separation between roof plate and dI1 interneurons is mediated by Notch activity downstream of retinoic acid, highlighting their critical role in establishing the roof plate-dI1 boundary. Within the peripheral branch, where absence of retinoic acid resulted in neural crest production and emigration extending into the roof plate stage, sensory progenitors failed to separate from melanocytes leading to formation of a common glia-melanocyte cell with aberrant migratory patterns. Together, we uncover and characterize a molecular mechanism responsible for segregation of dorsal neural fates during development.
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Project description:Regional specificity of stem cell-derived astrocytes is believed to be an important prerequisite for their applications in disease modelling and cell-based therapies. The regional identity of these astrocytes is often defined by the positional characteristics of their antecedent, stem cell-derived neural progenitors patterned to a fate of interest, with the assumption that the positional specification is to be preserved by the derived astrocytes. Using a human iPSC line designed for tracing midbrain floor plate derivatives, here we show that lineage composition of the derived astrocytes is not a faithful recapitulation of the founder progenitor population, as demonstrated by the loss of floor plate differentiated progeny in the final astrocyte products. Using deep single cell RNA sequencing, we identified distinct transcriptomic signatures of midbrain floor plate-derived astrocytes. Our study highlights the need for rigorous characterisation of PSC-derived regional astrocytes and provides a valuable resource for assessing midbrain floor plate-derived human astrocytes.
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Project description:The data revealed differential expression between floor plate and ventral lateral region in E10.5 mouse embryo midbrain. Several differentially expressed genes in these regions have been reported in the literature, demonstrating reliability of tissue dissection. Midbrain floor plate and non-overlapping adjacent ventral lateral region of mouse E10.5 embryo midbrain was dissected. Each sample was a pool from 6 embryos. Three replicates for each region were used for the experiment.
2011-05-18 | E-GEOD-25178 | biostudies-arrayexpress
Project description:In order to obtain the transcriptomic information about roof/dorsal and floor/ventral endothelial cells (ECs) of the dorsal aorta (DA) in zebrafish, we isolated single ECs from the DA roof and the floor respectively using the Tg(flk1:eGFP;flk1:NLS-Eos) zebrafish after photoconversion, and then performed scRNA sequencing. These single ECs were isolated at two different time points, 21 hpf and 28 hpf, when the lumen of the DA is established and the EHT begins , respectively.
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Project description:The data revealed differential expression between floor plate and ventral lateral region in E10.5 mouse embryo midbrain. Several differentially expressed genes in these regions have been reported in the literature, demonstrating reliability of tissue dissection.
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Project description:RFX3 and RFX4 were defined as transcription factors (TFs) with enriched TF binding sites in cis-regulatory elements that are activated during the conversion of human embryonic stem cells (hESCs) into ventral telencephalic MGE-like patterned neuronal precursors. Therefore, we conducted CRISPRi-mediated knockdown of RFX3 or RFX4 and profiled changes in gene expression in MGE-like ventral telencephalic progenitors by RNA-seq. This analysis revealed that RFX3 and RFX4 play important roles in cortical interneuron development, specifically during the transition from mitotically cycling neuronal precursors into post mitotic neurons.
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Project description:Floor plate-derived extracellular signaling molecules, including canonical axon guidance cues of the Netrin family, control neuronal circuit organization. Despite the importance of the floor plate as an essential signaling centre in the developing vertebrate central nervous system, no systematic approach to identify binding partners for floor plate-expressed cellsurface and secreted proteins has been carried out. Here, we used a high-throughput assay to discover extracellular protein-protein interactions, which likely take place in the zebrafish floor plate microenvironment. The assembled floor plate network contains 47 interactions including the hitherto not reported interaction between Netrin-1 and Draxin. We further characterized this interaction, narrowed down the binding interface, and demonstrated that Draxin competes with Netrin receptors for binding to Netrin-1. Our results suggest that Draxin functions as an extracellular Netrin signaling modulator in vertebrates. A reciprocal gradient of Draxin might shape or sharpen the active Netrin gradient, thereby critically modulating its effect.
2015-05-31 | E-MTAB-3609 | biostudies-arrayexpress
Project description:The Drosophila CNS consists of a bilaterally symmetric group of neurons separated by a discrete group of CNS midline cells. The specification of the CNS midline cell lineage requires transcription of the single-minded gene. Genetic evidence suggests that a group of transcription factors, including Dorsal, Snail, Twist, and Daughterless:: Scute, is required for initial single-minded transcription. Comparison of the DNA sequences of the single-minded gene regulatory regions between two Drosophila species reveals conserved sequence elements. Biochemical studies using purified proteins indicate that a number of these conserved sequences represent binding sites for Dorsal, Snail, and Twist. In vitro mutagenesis combined with germline transformation indicates that these binding sites are required in vivo for single-minded mesectodermal transcription. These results show that single-minded transcription and, thus, CNS midline specification is directly controlled by dorsal/ventral patterning transcription factors. They also suggest a model in which multiple transcriptional activators function in a cooperative, concentration-dependent mode in combination with a transcriptional repressor to restrict single-minded transcription to the CNS midline precursor cells.
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Project description:The availability of specific markers expressed in different regions of the developing nervous system provides a useful tool to illuminate their development, regulation and function. We have identified by expression profiling a putative non-coding RNA, Rmst, that exhibits prominent expression in the midbrain floor plate region, the isthmus and the roof plate of the anterior neural tube. At the developmental stage when the ventral dopaminergic neuron territory is being established, Rmst expression appears to be restricted to the presumptive dopaminergic neurons of the ventral tegmental area that lies close to the ventral midline. Thus this study presents Rmst as a novel marker for the developing dopaminergic neurons in the mesencephalic floor plate as well as a marker for the dorsal midline cells of the anterior neural tube and the isthmic organizer.
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