Organogenesis relies on SoxC transcription factors for the survival of neural and mesenchymal progenitors.
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ABSTRACT:
SUBMITTER: Bhattaram P
PROVIDER: S-EPMC2892298 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:During organogenesis, neural and mesenchymal progenitor cells give rise to many cell lineages, but their molecular requirements for self-renewal and lineage decisions are incompletely understood. Here we show that their survival critically relies on the redundantly acting SoxC transcription factors Sox4, Sox11 and Sox12. The more SoxC alleles are deleted in mouse embryos, the more severe and widespread organ hypoplasia is. SoxC triple-null embryos die at mid-gestation unturned and tiny, with normal patterning and lineage specification, but with massively dying neural and mesenchymal progenitor cells. Specific inactivation of SoxC genes in neural and mesenchymal cells leads to selective apoptosis of these cells, suggesting SoxC cell-autonomous roles. Tead2 functionally interacts with the SoxC genes in embryonic development, and is a direct target of the SoxC proteins. The SoxC genes therefore ensure neural and mesenchymal progenitor cell survival and act in part by activating this transcriptional mediator of the Hippo signaling pathway. During organogenesis, neural and mesenchymal progenitor cells give rise to many cell lineages, but their molecular requirements for self-renewal and lineage decisions are incompletely understood. Here we show that their survival critically relies on the redundantly acting SoxC transcription factors Sox4, Sox11 and Sox12. The more SoxC alleles are deleted in mouse embryos, the more severe and widespread organ hypoplasia is. SoxC triple-null embryos die at mid-gestation unturned and tiny, with normal patterning and lineage specification, but with massively dying neural and mesenchymal progenitor cells. Specific inactivation of SoxC genes in neural and mesenchymal cells leads to selective apoptosis of these cells, suggesting SoxC cell-autonomous roles. Tead2 functionally interacts with the SoxC genes in embryonic development, and is a direct target of the SoxC proteins. The SoxC genes therefore ensure neural and mesenchymal progenitor cell survival and act in part by activating this transcriptional mediator of the Hippo signaling pathway. Total RNA isolated from limb bud cells in culture treated with Cre recombinase expressing adenovirus to inactivate floxed SoxC genes was compared to total RNA isolated from cells treated with LacZ expressing adenovirus as well as untreated cells as controls.
2010-04-28 | E-GEOD-20740 | biostudies-arrayexpress
Project description:During organogenesis, neural and mesenchymal progenitor cells give rise to many cell lineages, but their molecular requirements for self-renewal and lineage decisions are incompletely understood. Here we show that their survival critically relies on the redundantly acting SoxC transcription factors Sox4, Sox11 and Sox12. The more SoxC alleles are deleted in mouse embryos, the more severe and widespread organ hypoplasia is. SoxC triple-null embryos die at mid-gestation unturned and tiny, with normal patterning and lineage specification, but with massively dying neural and mesenchymal progenitor cells. Specific inactivation of SoxC genes in neural and mesenchymal cells leads to selective apoptosis of these cells, suggesting SoxC cell-autonomous roles. Tead2 functionally interacts with the SoxC genes in embryonic development, and is a direct target of the SoxC proteins. The SoxC genes therefore ensure neural and mesenchymal progenitor cell survival and act in part by activating this transcriptional mediator of the Hippo signaling pathway. During organogenesis, neural and mesenchymal progenitor cells give rise to many cell lineages, but their molecular requirements for self-renewal and lineage decisions are incompletely understood. Here we show that their survival critically relies on the redundantly acting SoxC transcription factors Sox4, Sox11 and Sox12. The more SoxC alleles are deleted in mouse embryos, the more severe and widespread organ hypoplasia is. SoxC triple-null embryos die at mid-gestation unturned and tiny, with normal patterning and lineage specification, but with massively dying neural and mesenchymal progenitor cells. Specific inactivation of SoxC genes in neural and mesenchymal cells leads to selective apoptosis of these cells, suggesting SoxC cell-autonomous roles. Tead2 functionally interacts with the SoxC genes in embryonic development, and is a direct target of the SoxC proteins. The SoxC genes therefore ensure neural and mesenchymal progenitor cell survival and act in part by activating this transcriptional mediator of the Hippo signaling pathway.
2010-04-15 | GSE20740 | GEO
Project description:Glaucoma and other optic neuropathies result in optic nerve degeneration and the loss of retinal ganglion cells (RGCs) through complex signaling pathways. Although the mechanisms that regulate RGC development remain unclear, uncovering novel developmental pathways may support new strategies to regenerate the optic nerve or replace RGCs. Here we review recent studies that provide strong evidence that the Sry-related high-mobility-group C (SoxC) subfamily of transcription factors (TFs) are necessary and sufficient for axon guidance and RGC fate specification. These findings also uncover novel SoxC-dependent mechanisms that serve as master regulators during important steps of RGC development. For example, we review work showing that SoxC TFs regulate RGC axon guidance and direction through the optic chiasm towards their appropriate targets in the brain. We also review work demonstrating that Sox11 subcellular localization is, in part, controlled through small ubiquitin-like post-translational modifier (SUMO) and suggest compensatory cross-talk between Sox4 and Sox11. Furthermore, Sox4 overexpression is shown to positively drive RGC differentiation in human induced pluripotent stem cells (hiPSCs). Finally, we discuss how these findings may contribute to the advancement of regenerative and cell-based therapies to treat glaucoma and other optic nerve neuropathies.
| S-EPMC5558478 | biostudies-literature
Project description:Early human embryonic stem cell (hESC)-derived neural populations consist of various embryonic neural progenitors (ENPs) with broad neural developmental propensity. Here, we sought to directly convert human somatic cells into ENP-like phenotypes using hESC-ENP-enriched neural transcription factors (TFs). We demonstrated that induced ENP could be efficiently converted from human fibroblasts using two TF combinations. The iENPs exhibit cellular and molecular characteristics resembling hESC-ENPs and can give rise to astrocytes, oligodendrocytes, and functional neuronal subtypes of the central and peripheral nervous system. Nevertheless, our analyses further revealed that these two iENP populations differ in terms of their proliferation ability and neuronal propensity. Finally, we demonstrated that the iENPs can be induced from fibroblasts from patients with Huntington's disease and Alzheimer's disease, and the diseased iENPs and their neuronal derivatives recapitulated the hallmark pathological features of the diseases. Collectively, our results point toward a promising strategy for generating iENPs from somatic cells for disease modeling and future clinical intervention.
| S-EPMC5233298 | biostudies-literature
Project description:Hair cells, the mechanosensory receptors of the inner ear, underlie the senses of hearing and balance. Adult mammals cannot adequately replenish lost hair cells, whose loss often results in deafness or balance disorders. To determine the molecular basis of this deficiency, we investigated the development of a murine vestibular organ, the utricle. Here we show that two members of the SoxC family of transcription factors, Sox4 and Sox11, are down-regulated after the epoch of hair cell development. Conditional ablation of SoxC genes in vivo results in stunted sensory organs of the inner ear and loss of hair cells. Enhanced expression of SoxC genes in vitro conversely restores supporting cell proliferation and the production of new hair cells in adult sensory epithelia. These results imply that SoxC genes govern hair cell production and thus advance these genes as targets for the restoration of hearing and balance.
| S-EPMC4653225 | biostudies-literature
Project description:The related transcription factors SOX11, SOX4 and SOX12 (classified as the SOXC family) compete for the same target genes. SOX11 is expressed in most mantle cell lymphomas (MCL) but a small subset is, like normal lymphocytes, SOX11 negative. Here we report the variable expression of SOX4 and high expression of SOX12 in MCL compared to non-malignant tissue. Our results show that the expression of the SOXC genes is highly correlated in SOX11 positive MCL. SOX11 expression is epigenetically regulated but there are partly conflicting results regarding the underlying mechanisms. Here we report that the SOX11 promoter region is hypomethylated in both MCL and normal B-lymphocytes. Methylation at other sites is important for sustaining high SOX11 in MCL since treatment with 5-azacytidine decreased SOX11 levels in SOX11 positive MCL cell lines: Granta519 and Rec1. Furthermore, 5-azacytidine treatment of the SOX11 negative MCL cell line, JVM2, induced SOX4 but not SOX11.
| S-EPMC3590557 | biostudies-literature
Project description:Growth plates are specialized cartilage structures that ensure the elongation of most skeletal primordia during vertebrate development. They are made by chondrocytes that proliferate in longitudinal columns and then progress in a staggered manner towards prehypertrophic, hypertrophic and terminal maturation. Complex molecular networks control the formation and activity of growth plates, but remain incompletely understood. We investigated here the importance of the SoxC genes, which encode the SOX4, SOX11 and SOX12 transcription factors, in growth plates. We show that the three genes are expressed robustly in perichondrocytes and weakly in growth plate chondrocytes. SoxC(Prx1Cre) mice, which deleted SoxC genes in limb bud skeletogenic mesenchyme, were born with tiny appendicular cartilage primordia because of failure to form growth plates. In contrast, SoxC(Col2Cre) and SoxC(ATC) mice, which deleted SoxC genes primarily in chondrocytes, were born with mild dwarfism and fair growth plates. Chondrocytes in the latter mutants matured normally, but formed irregular columns, proliferated slowly and died ectopically. Asymmetric distribution of VANGL2 was defective in both SoxC(Prx1Cre) and SoxC(ATC) chondrocytes, indicating impairment of planar cell polarity, a noncanonical WNT signaling pathway that controls growth plate chondrocyte alignment, proliferation and survival. Accordingly, SoxC genes were necessary in perichondrocytes for expression of Wnt5a, which encodes a noncanonical WNT ligand required for growth plate formation, and in chondrocytes and perichondrocytes for expression of Fzd3 and Csnk1e, which encode a WNT receptor and casein kinase-1 subunit mediating planar cell polarity, respectively. Reflecting the differential strengths of the SOXC protein transactivation domains, SOX11 was more powerful than SOX4, and SOX12 interfered with the activity of SOX4 and SOX11. Altogether, these findings provide novel insights into the molecular regulation of skeletal growth by proposing that SOXC proteins act cell- and non-cell-autonomously in perichondrocytes and chondrocytes to establish noncanonical WNT signaling crosstalk essential for growth plate induction and control.
| S-EPMC4540656 | biostudies-literature
Project description:OBJECTIVE:Fibroblast-like synoviocytes (FLS) produce key synovial fluid and tissue components to ensure joint integrity under healthy conditions, whereas they become cancer-like and aggressively contribute to joint degeneration in inflammatory arthritis. The aim of this study was to determine whether the SOXC transcription factors SOX4 and SOX11, whose functions are critical in joint development and many cancer types, contribute to FLS activities under normal and inflammatory conditions. METHODS:We inactivated the SOXC genes in FLS from adult mice and studied the effect on joint homeostasis and tumor necrosis factor (TNF)-induced arthritis. We used primary cells and synovial biopsy specimens from arthritis patients to analyze the interactions between inflammatory signals and SOXC proteins. RESULTS:Postnatal inactivation of the SOXC genes had no major effect on joint integrity in otherwise healthy mice. However, it hampered synovial hyperplasia and joint degeneration in transgenic mice expressing human TNF. These effects were explained by the ability of SOX4/11 to amplify the pathogenic impact of TNF on FLS by increasing their survival and migration. SOXC RNA levels were not changed by TNF and other proinflammatory cytokines, but SOXC proteins were strongly stabilized and able to potentiate the TNF-induced up-regulation of genes involved in FLS transformation. Substantiating the relevance of these findings in human disease, SOXC protein levels, but not RNA levels, were significantly higher in inflamed synovium than in noninflamed synovium from arthritis patients. CONCLUSION:SOXC proteins are targets and pivotal mediators of proinflammatory cytokines during FLS transformation in arthritic diseases. Targeting of these proteins could thus improve current strategies to treat arthritic diseases and possibly other inflammatory diseases.
| S-EPMC5826855 | biostudies-literature
Project description:Transcription factors control cell identity by regulating diverse developmental steps such as differentiation and axon guidance. The mammalian binocular visual circuit is comprised of projections of retinal ganglion cells (RGCs) to ipsilateral and contralateral targets in the brain. A transcriptional code for ipsilateral RGC identity has been identified, but less is known about the transcriptional regulation of contralateral RGC development. Here we demonstrate that SoxC genes (Sox4, 11, and 12) act on the progenitor-to-postmitotic transition to implement contralateral, but not ipsilateral, RGC differentiation, by binding to Hes5 and thus repressing Notch signaling. When SoxC genes are deleted in postmitotic RGCs, contralateral RGC axons grow poorly on chiasm cells in vitro and project ipsilaterally at the chiasm midline in vivo, and Plexin-A1 and Nr-CAM expression in RGCs is downregulated. These data implicate SoxC transcription factors in the regulation of contralateral RGC differentiation and axon guidance.
| S-EPMC5346053 | biostudies-literature
Project description:Sox11 deletion mice are known to exhibit developmental defects of craniofacial skeletal malformations, asplenia, and hypoplasia of the lung, stomach, and pancreas. Despite the importance of Sox11 in the developing skeleton, the role of Sox11 in osteogenesis has not been studied yet. In this study, we identified that Sox11 is an important transcription factor for regulating the proliferation and survival of osteoblast precursor cells as well as the self-renewal potency of mesenchymal progenitor cells via up-regulation of Tead2. Furthermore, Sox11 also plays an important role in the segregation of functional osteoblast lineage progenitors from osteochondrogenic progenitors. Facilitation of osteoblast differentiation from mesenchymal cells was achieved by enhanced expression of the osteoblast lineage specific transcription factors Runx2 and Osterix. Morpholino-targeted disruption of Sox11 in zebrafish impaired organogenesis, including the bones, which were under mineralized. These results indicated that Sox11 plays a crucial role in the proliferation and survival of mesenchymal and osteoblast precursors by Tead2, and osteogenic differentiation by regulating Runx2 and Osterix.
| S-EPMC3757203 | biostudies-literature