Evidence for Baseline Retinal Pigment Epithelium Pathology in the Trp1-Cre Mouse

Thanos, Aristomenis; Morizane, Yuki; Murakami, Yusuke; Giani, Andrea; Mantopoulos, Dimosthenis; Kayama, Maki; Roh, Miin; Michaud, Norman; Pawlyk, Basil; Sandberg, Michael A.; Young, Lucy H.; Miller, Joan W.; Vavvas, Demetrios G.

doi:10.1016/j.ajpath.2012.01.017

Cited by 34 publications

(34 citation statements)

References 40 publications

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“…It is noteworthy to mention that a recent study investigated the affect of TrpCre-1 on RPE biology. In this paper, the authors showed that Cre alone caused a decrease in cell density with an increase in abnormal cell morphology [44]. We also saw this phenomenon in our Trp1-Cre tg/o RPEs, but loss of ATR greatly augmented these effects.…”

Section: Discussionsupporting

confidence: 66%

ATR Suppresses Endogenous DNA Damage and Allows Completion of Homologous Recombination Repair

et al. 2014

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DNA replication fork stalling or collapse that arises from endogenous damage poses a serious threat to genome stability, but cells invoke an intricate signaling cascade referred to as the DNA damage response (DDR) to prevent such damage. The gene product ataxia telangiectasia and Rad3-related (ATR) responds primarily to replication stress by regulating cell cycle checkpoint control, yet it’s role in DNA repair, particularly homologous recombination (HR), remains unclear. This is of particular interest since HR is one way in which replication restart can occur in the presence of a stalled or collapsed fork. Hypomorphic mutations in human ATR cause the rare autosomal-recessive disease Seckel syndrome, and complete loss of Atr in mice leads to embryonic lethality. We recently adapted the in vivo murine pink-eyed unstable (pun) assay for measuring HR frequency to be able to investigate the role of essential genes on HR using a conditional Cre/loxP system. Our system allows for the unique opportunity to test the effect of ATR loss on HR in somatic cells under physiological conditions. Using this system, we provide evidence that retinal pigment epithelium (RPE) cells lacking ATR have decreased density with abnormal morphology, a decreased frequency of HR and an increased level of chromosomal damage.

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Section: Discussionsupporting

confidence: 66%

ATR Suppresses Endogenous DNA Damage and Allows Completion of Homologous Recombination Repair

et al. 2014

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“…S1). The Trp1-Cre line exhibits some degree of RPE degeneration in the eye as recently reported (34), but its CB region is normal. The mutant CB phenotype is very consistent on the ventral side of the eye, but is more variable on the dorsal side ranging from no morphogenesis to normal morphogenesis (Fig.…”

Section: Notch2mentioning

confidence: 73%

Notch2 regulates BMP signaling and epithelial morphogenesis in the ciliary body of the mouse eye

Zhou

Tanzie

Yan

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The ciliary body (CB) of the mammalian eye is responsible for secreting aqueous humor to maintain intraocular pressure, which is elevated in the eyes of glaucoma patients. It contains a folded two-layered epithelial structure comprising the nonpigmented inner ciliary epithelium (ICE), the pigmented outer ciliary epithelium (OCE), and the underlying stroma. Although the CB has an important function in the eye, its morphogenesis remains poorly studied. In this study, we show that conditional inactivation of the Jagged 1 (Jag1)-Notch2 signaling pathway in the developing CB abolishes its morphogenesis. Notch2 is expressed in the OCE of the CB, whereas Jag1 is expressed in the ICE. Conditional inactivation of Jag1 in the ICE or Notch2 in the OCE disrupts CB morphogenesis, but neither affects the specification of the CB region. Notch2 signaling in the OCE is required for promoting cell proliferation and maintaining bone morphogenetic protein (BMP) signaling, both of which have been suggested to be important for CB morphogenesis. Although Notch and BMP signaling pathways are known to crosstalk via the interaction between their downstream transcriptional factors, this study suggests that Notch2 maintains BMP signaling in the OCE possibly by repressing expression of secreted BMP inhibitors. Based on our findings, we propose that Jag1-Notch2 signaling controls CB morphogenesis at least in part by regulating cell proliferation and BMP signaling.T he mammalian eye is composed of the anterior segment, the posterior retina and the vitreous. The anterior segment consists of cornea, lens, and ciliary body (CB), whereas the posterior retina contains six types of retinal neurons and Müller glial cells, which are organized into three distinct cell layers. The light passes through the cornea and is then focused by the lens and detected by photoreceptors in the retina. Both the aqueous humor anteriorly and the vitreous humor posteriorly function together to sustain intraocular pressure (IOP) in the eye and thereby maintain its shape. Pressure regulation is particularly important because abnormally high IOP is a major risk factor for glaucoma (1). In the eye, the CB is responsible for producing aqueous humor (2). Although high IOP is often attributed to the blockage of the drainage system for the vitreous, known as the trabecular meshwork, abnormal CB function might also contribute to high IOP formation because of excess aqueous humor production. Finally, contraction of the muscles in the CB controls lens accommodation for near versus far vision. Despite its important biological functions and potential medical significance, the formation and development of the CB remain poorly studied.The CB contains two layers of apically adhered epithelial sheets, the pigmented outer ciliary epithelium (OCE) and the nonpigmented inner ciliary epithelium (ICE), and the underlying stroma (2). It forms at the periphery of the developing optic cup and first segregates from the retina and then from the iris. One previous study suggested that blood vesse...

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“…The cellular production of the Cre recombinase has been reported to result in toxicity and altered phenotype in certain cell types3233. To exclude this and the haploinsufficiency of the Lysm allele due to the knock-in of Cre34, we utilized flow cytometry to quantify the infiltrating myeloid subsets at peak disease, 18 hours post-EIU induction in Lysm + /Cre mice and their wild type littermate controls.…”

Section: Resultsmentioning

confidence: 99%

Hypoxia inducible factors are dispensable for myeloid cell migration into the inflamed mouse eye

Gardner¹,

Liyanage²,

Cristante³

et al. 2017

Sci Rep

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Hypoxia inducible factors (HIFs) are ubiquitously expressed transcription factors important for cell homeostasis during dynamic oxygen levels. Myeloid specific HIFs are crucial for aspects of myeloid cell function, including their ability to migrate into inflamed tissues during autoimmune disease. This contrasts with the concept that accumulation of myeloid cells at ischemic and hypoxic sites results from a lack of chemotactic responsiveness. Here we seek to address the role of HIFs in myeloid trafficking during inflammation in a mouse model of human uveitis. We show using mice with myeloid-specific Cre-deletion of HIFs that myeloid HIFs are dispensable for leukocyte migration into the inflamed eye. Myeloid-specific deletion of Hif1a, Epas1, or both together, had no impact on the number of myeloid cells migrating into the eye. Additionally, stabilization of HIF pathways via deletion of Vhl in myeloid cells had no impact on myeloid trafficking into the inflamed eye. Finally, we chemically induce hypoxemia via hemolytic anemia resulting in HIF stabilization within circulating leukocytes to demonstrate the dispensable role of HIFs in myeloid cell migration into the inflamed eye. These data suggest, contrary to previous reports, that HIF pathways in myeloid cells during inflammation and hypoxia are dispensable for myeloid cell tissue trafficking.

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Evidence for Baseline Retinal Pigment Epithelium Pathology in the Trp1-Cre Mouse

Cited by 34 publications

References 40 publications

ATR Suppresses Endogenous DNA Damage and Allows Completion of Homologous Recombination Repair

ATR Suppresses Endogenous DNA Damage and Allows Completion of Homologous Recombination Repair

Notch2 regulates BMP signaling and epithelial morphogenesis in the ciliary body of the mouse eye

Hypoxia inducible factors are dispensable for myeloid cell migration into the inflamed mouse eye

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