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Six3 and Six6 jointly regulate the identities and developmental trajectories of multipotent retinal progenitor cells in the embryonic mouse retina

ABSTRACT: Six3 and Six6 jointly regulate the identities and developmental trajectories of multipotent retinal progenitor cells in the embryonic mouse retina

PROVIDER: PRJNA1010790 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25820351_1.fastq.gz	Fastqsanger.gz
	SRR25820351_2.fastq.gz	Fastqsanger.gz
	SRR25820352_1.fastq.gz	Fastqsanger.gz
	SRR25820352_2.fastq.gz	Fastqsanger.gz

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Six3 and Six6 jointly regulate the identities and developmental trajectories of multipotent retinal progenitor cells in the embryonic mouse retina

Project description:Regulation of retinal differentiation in mammals is not adequately understood. Using single-cell RNA sequencing of control and Six3 and Six6 compound-mutant mouse embryonic eye-cups, we identified cell clusters and developmental trajectories jointly regulated by transcription factor Six3 and its close paralog Six6. In control retinas, naïve retinal progenitor cells had two major trajectories leading to ciliary margin cells and retinal neurons, respectively. The ciliary margin trajectory was directly from naïve retinal progenitor cells at G1 phase whereas the neuronal trajectory was through a neurogenic state marked by Atoh7 expression. Upon Six3 and Six6 dual deficiencies, both naïve and neurogenic retinal progenitors were defective, ciliary margin differentiation was enhanced, and multi-lineage neuronal differentiation was disrupted. An ectopic neuronal trajectory lacking the Atoh7+ state led to ectopic neurons. Additionally, opposing gradients of Wnt and Fgf signaling were perturbed. Our findings provide deeper insight into molecular mechanisms underlying early retinal differentiation in mammals.

2024-08-03 | GSE241946 | GEO

Six3 and Six6 are jointly required for the maintenance of multipotent retinal progenitors through both positive and negative regulation

Project description:Purpose: the goal of this experiment was to identify differentially expressed genes in Six3 null, Six6 null and Six3;Six6 compound null retinas by RNAsequencing. Method: Retinas were dissected out from the following E13.5 mouse embryos: 1) WT (Six3F/F; Six6+/+); 2) Six3 KO (Six3F/F; CAGGCre-ERTM; Six6+/+); 3) Six6 KO (Six3F/F; Six6–/–); 4) DKO (Six3F/F; CAGGCre-ERTM; Six6–/–). RNA was then extracted from the retinas and profiled using RNAsequencing. Results: RNA isolated from three pairs of retinas for each genotype group (181.2-792 ng, RIN>9) was used for library preparation using KAPA RNA HyperPrep Kit with RiboErase. Sequencing was run on Illumina HiSeq 2500 in 100-bp single-end high-output mode in the Einstein Epigenomics Core Facility. About 30 million reads were generated for each sample. Each genotype group initially had three biological replicates, but one Six6 KO replicate was later removed due to over duplication. After trimming adapters with Trim Galore (v. 0.3.7), RNA-Seq reads were aligned back to mouse genome mm10 using Tophat (v. 2.0.13). The number of reads mapped back to each gene was calculated with HTseq (v.0.6.1) using Refseq gene annotation (downloaded from the UCSC genome browser in 03/17). The Cuffdiff in Cufflinks package (v. 2.2.1) was used to generate FPKM values. We identified 13498 transcripts with FPKM value >1 in at least one of samples. Deseq2 was used to determine the differentially expressed genes (DEGs) with FDR less than 0.05 as a cutoff.

2018-11-14 | GSE115258 | GEO

Six3 and Six6 are jointly required for the maintenance of multipotent retinal progenitors through both positive and negative regulation

Project description:Six3 and Six6 are jointly required for the maintenance of multipotent retinal progenitors through both positive and negative regulation

| PRJNA474480 | ENA

Six3 and Six6 Are Jointly Required for the Maintenance of Multipotent Retinal Progenitors through Both Positive and Negative Regulation.

Project description:Gene regulation of multipotent neuroretinal progenitors is partially understood. Through characterizing Six3 and Six6 double knockout retinas (DKOs), we demonstrate Six3 and Six6 are jointly required for the maintenance of multipotent neuroretinal progenitors. Phenotypes in DKOs were not found in either Six3 nulls or Six6 nulls. At the far periphery, ciliary margin (CM) markers Otx1 and Cdon together with Wnt3a and Fzd1 were ectopically upregulated, whereas neuroretinal progenitor markers Sox2, Notch1, and Otx2 were absent or reduced. At the mid periphery, multi-lineage differentiation was defective. The gene set jointly regulated by Six3 and Six6 significantly overlapped with the gene networks regulated by WNT3A, CTNNB1, POU4F2, or SOX2. Stimulation of Wnt/β-catenin signaling by either Wnt-3a or a GS3Kβ inhibitor promoted CM progenitors at the cost of neuroretinal identity at the periphery of eyecups. Therefore, Six3 and Six6 together directly or indirectly suppress Wnt/β-catenin signaling but promote retinogenic factors for the maintenance of multipotent neuroretinal progenitors.

| S-EPMC6317371 | biostudies-literature

SIX6 knockdown in Jurkat-Cas9 T-ALL cell line

Project description:T cell acute lymphoblastic leukemia (T-ALL) is a hematological malignancy strongly affected by the abnormal activity of transcription factors. Here we report a high expression of developmental transcription factor SIX6 in TAL1 subtype of T-ALL. Our data indicates that this high expression is directly regulated by binding of TAL1 and GATA3 transcription factors into an upstream enhancer element. We also looked into the potential targets of SIX6 in T-ALL and Crispr-cas9 mediated knockout of SIX6 in Jurkat cells caused significant changes in the expression of multiple genes, including genes related to mTOR signaling. In two independent patient cohorts, the high SIX6 expression shows a trend of less favourable prognosis. However, the knockout of SIX6 was not enough to have an effect on proliferation, cell cycle or viability of the Jurkat cells and overexpression of SIX6 in the T-ALL zebrafish model didn’t influence the progression of the disease. Our results show that high expression of SIX6 has a trend towards a less favourable outcome, but SIX6 doesn’t have an independent oncogenic role in T-ALL.

2020-04-15 | GSE148658 | GEO

Finding genomic targets of transcription factor Six3 in neural stem cells.

Project description:Pro-neural transcription factor Six3 has been implicated in neuronal differentiation. We established primary neural stem cell with Six3 overexpression, and utilized CUT&RUN to profile genomic loci bound by Six3.

2022-07-17 | GSE208169 | GEO

SIX3 and SIX6 interact with GEMININ via C-terminal regions.

Project description:The histoarchitecture and function of eye and forebrain depend on a well-controlled balance between cell proliferation and differentiation. For example, the binding of the cell cycle regulator GEMININ to CDT1, which is a part of the pre-replication complex, promotes cell differentiation. Homeodomain transcription factors SIX3 and SIX6 also interact with GEMININ of which SIX3-GEMININ interaction promotes cell proliferation, whereas the nature of SIX6-GEMININ interaction has not been studied to date. We investigated SIX3/SIX6 and GEMININ interactions using bimolecular fluorescence complementation, surface plasmon resonance and isothermal titration calorimetry. Interactions between SIX3/SIX6 and GEMININ were detected in mammalian cells in culture. The presence of the C-terminal regions of SIX3 and SIX6 proteins, but not their SIX domains or homeodomains as previously thought, were required for interaction with GEMININ. Interestingly, the disordered C- and N- terminal regions of GEMININ were involved in binding to SIX3/SIX6. The coiled-coil region of GEMININ, which is the known protein-binding domain and also interacts with CDT1, was not involved in GEMININ-SIX3/SIX6 interaction. Using SPR and ITC, SIX3 bound GEMININ with a micromolar affinity and the binding stoichiometry was 1:2 (SIX3 - GEMININ). The present study gives new insights into the binding properties of SIX proteins, especially the role of their variable and disordered C-terminal regions.

| S-EPMC6895700 | biostudies-literature

SIX6 regulation in human optic vesicles is mediated by early microenvironmenta factors

Project description:Human pluripotent stem cells (PSCs) represent an exciting tool to investigate the mechanisms of human eye development and to build models of human retinal disease. When grown in 3D, these cells can self-organize into laminar organized retinas; however, significant variation in the size, shape and composition of individual organoids exists, and this variation can create challenges. Neither the microenvironment nor the timing of critical growth factors driving eye formation or retinogenesis are fully understood. To explore the dynamics of early retinal organoid development, we have developed a SIX6-GFP reporter line that enables the systematic optimization of early eye field development, allowing for the identification of conditions that favor optic development. We found that SIX6 expression in 3D optic structures is influenced by small molecules regulating SHH and WNT signaling in a dose and time dependent fashion. In addition, we demonstrated that hypoxic growth conditions favor SIX6 expression, and promote eye formation. The systematic optimization of these pathways leads to optic vesicles with robust SIX6 expression and global gene expression profiles consistent with a retinal identity. The use of stem cell derived human retinal organoids with a real time marker for retinogenesis, therefore, represents an important model for probing the mechanisms of early human eye development.

2021-10-25 | GSE148168 | GEO

A SIX6 reporter for studies of early optic development

Project description:Human pluripotent stem cells represent an exciting tool to investigate the mechanisms of human eye development and to build human models of retinal dystrophy. To explore the dynamics of early eye development in a carefully controlled setting and optimize this process, we have developed an eyefield expressed SIX6-GFP reporter that enables the systematic optimization of early eye-field development allowing the identification of conditions that favor early optic development.

2021-08-31 | GSE179260 | GEO

SIX2 and SIX3 coordinately regulate functional maturity and fate of human pancreatic β cells [RNA-seq]

Project description:Transcriptomic profiling by high-throughput sequencing of primary human Beta cells following SIX2 or SIX3 loss of function.

2021-01-26 | GSE164626 | GEO