Pax6 is misexpressed in Sox1 null lens fiber cells

Donner, Amy; Ko, Fang; Episkopou, Vasso; Maas, Richard L.

doi:10.1016/j.modgep.2007.01.001

Cited by 17 publications

(14 citation statements)

References 40 publications

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“…Given that these two tissues are the most severely affected in Sox2 HYP embryos, these expression profiles fit a model in which (i) a certain degree of SOXB1 dosage is required in all regions of the neural epithelium; and (ii) the neural retina and the ventral midline are the most sensitive tissues to SOX2-deficiency. The phenotypes of SOX3 and SOX1-deficient mice are consistent with this hypothesis (Malas et al, 2003; Rizzoti et al, 2004; Donner et al, 2007). …”

Section: Discussionsupporting

confidence: 78%

SOX2 hypomorphism disrupts development of the prechordal floor and optic cup

Langer

Taranova

Sulik

et al. 2012

Mechanisms of Development

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Haploinsufficiency for the HMG-box transcription factor SOX2 results in abnormalities of the human ventral forebrain and its derivative structures. These defects include anophthalmia (absence of eye), microphthalmia (small eye) and hypothalamic hamartoma (HH), an overgrowth of the ventral hypothalamus. To determine how Sox2 deficiency affects the morphogenesis of the ventral diencephalon and eye, we generated a Sox2 allelic series (Sox2IR, Sox2LP, and Sox2EGFP), allowing for the generation of mice that express germline hypomorphic levels (<40%) of SOX2 protein and that faithfully recapitulate SOX2 haploinsufficient human phenotypes. We find that Sox2 hypomorphism significantly disrupts the development of the posterior hypothalamus, resulting in an ectopic protuberance of the prechordal floor, an upregulation of Shh signaling, and abnormal hypothalamic patterning. In the anterior diencephalon, both the optic stalks and optic cups (OC) of Sox2 hypomorphic (Sox2HYP) embryos are malformed. Furthermore, Sox2HYP eyes exhibit a loss of neural potential and coloboma, a common phenotype in SOX2 haploinsufficient humans that has not been described in a mouse model of SOX2 deficiency. These results establish for the first time that germline Sox2 hypomorphism disrupts the morphogenesis and patterning of the hypothalamus, optic stalk, and the early OC, establishing a model of the development of the abnormalities that are observed in SOX2 haploinsufficient humans.

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Section: Discussionsupporting

confidence: 78%

SOX2 hypomorphism disrupts development of the prechordal floor and optic cup

Langer

Taranova

Sulik

et al. 2012

Mechanisms of Development

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“…The Sox transcription factor and its interacting partner bind to adjacent DNA sequences in promoter/enhancer of target genes to regulate their expression. Several Sox2 partners have been identified in various cell types (Table 1) [4,34,35,41,[47][48][49][50] . The most studied Sox2 partner is Oct4 in PSCs.…”

Section: Differentiationmentioning

confidence: 99%

Sox2, a key factor in the regulation of pluripotency and neural differentiation

Zhang

Cui

2014

WJSC

327

227

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Sex determining region Y-box 2 (Sox2), a member of the SoxB1 transcription factor family, is an important transcriptional regulator in pluripotent stem cells (PSCs). Together with octamer-binding transcription factor 4 and Nanog, they co-operatively control gene expression in PSCs and maintain their pluripotency. Furthermore, Sox2 plays an essential role in somatic cell reprogramming, reversing the epigenetic configuration of differentiated cells back to a pluripotent embryonic state. In addition to its role in regulation of pluripotency, Sox2 is also a critical factor for directing the differentiation of PSCs to neural progenitors and for maintaining the properties of neural progenitor stem cells. Here, we review recent findings concerning the involvement of Sox2 in pluripotency, somatic cell reprogramming and neural differentiation as well as the molecular mechanisms underlying these roles. Zhang S, Cui W. Sox2, a key factor in the regulation of pluripotency and neural differentiation. World J Stem Cells

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“…Prox1, Sox1, and the large Maf protein, Maf (c-Maf) positively regulate crystallin-encoding genes in fiber cells (Audette et al, 2016; Donner et al, 2007b; Kawauchi et al, 1999; Kim et al, 1999; Nishiguchi et al, 1998; Ring et al, 2000; Wigle et al, 1999). Interestingly, Mafg and Mafk are linked to early-onset age-related cataract and control non-crystallin cataract genes (Agrawal et al, 2015).…”

Section: Molecular Biology Of Lens Development: a Brief Overviewmentioning

confidence: 99%

Systems biology of lens development: A paradigm for disease gene discovery in the eye

Anand

Lachke

2017

Experimental Eye Research

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Over the past several decades, the biology of the developing lens has been investigated using molecular genetics-based approaches in various vertebrate model systems. These efforts, involving target gene knockouts or knockdowns, have led to major advances in our understanding of lens morphogenesis and the pathological basis of cataracts, as well as of other lens related eye defects. In particular, we now have a functional understanding of regulators such as Pax6, Six3, Sox2, Oct1 (Pou2f1), Meis1, Pnox1, Zeb2 (Sip1), Mab21l1, Foxe3, Tfap2a (Ap2-alpha), Pitx3, Sox11, Prox1, Sox1, c-Maf, Mafg, Mafk, Hsf4, Fgfrs, Bmp7, and Tdrd7 in this tissue. However, whether these individual regulators interact or their targets overlap, and the significance of such interactions during lens morphogenesis, is not well defined. The arrival of high-throughput approaches for gene expression profiling (microarrays, RNA-sequencing (RNA-seq), etc.), which can be coupled with chromatin immunoprecipitation (ChIP) or RNA immunoprecipitation (RIP) assays, along with improved computational resources and publically available datasets (e.g. those containing comprehensive protein-protein, protein-DNA information), presents new opportunities to advance our understanding of the lens tissue on a global systems level. Such systems-level knowledge will lead to the derivation of the underlying lens gene regulatory network (GRN), defined as a circuit map of the regulator-target interactions functional in lens development, which can be applied to expedite cataract gene discovery. In this review, we cover the various systems-level approaches such as microarrays, RNA-seq, and ChIP that are already being applied to lens studies and discuss strategies for assembling and interpreting these vast amounts of high-throughput information for effective dispersion to the scientific community. In particular, we discuss strategies for effective interpretation of this new information in the context of the rich knowledge obtained through the application of traditional single-gene focused experiments on the lens. Finally, we discuss our vision for integrating these diverse high-throughput datasets in a single web-based user-friendly tool iSyTE (integrated Systems Tool for Eye gene discovery) – a resource that is already proving effective in the identification and characterization of genes linked to lens development and cataract. We anticipate that application of a similar approach to other ocular tissues such as the retina and the cornea, and even other organ systems, will significantly impact disease gene discovery.

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Pax6 is misexpressed in Sox1 null lens fiber cells

Cited by 17 publications

References 40 publications

SOX2 hypomorphism disrupts development of the prechordal floor and optic cup

SOX2 hypomorphism disrupts development of the prechordal floor and optic cup

Sox2, a key factor in the regulation of pluripotency and neural differentiation

Systems biology of lens development: A paradigm for disease gene discovery in the eye

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