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Matrix Metalloproteinase 14 in the Zebrafish: An Eye on Retinal and Retinotectal Development  [PDF]
Els Janssens, Djoere Gaublomme, Lies De Groef, Veerle M. Darras, Lut Arckens, Nathalie Delorme, Filip Claes, Inge Van Hove, Lieve Moons
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0052915
Abstract: Background Matrix metalloproteinases (MMPs) are members of the metzincin superfamily of proteinases that cleave structural elements of the extracellular matrix and many molecules involved in signal transduction. Although there is evidence that MMPs promote the proper development of retinotectal projections, the nature and working mechanisms of specific MMPs in retinal development remain to be elucidated. Here, we report a role for zebrafish Mmp14a, one of the two zebrafish paralogs of human MMP14, in retinal neurogenesis and retinotectal development. Results Whole mount in situ hybridization and immunohistochemical stainings for Mmp14a in developing zebrafish embryos reveal expression in the optic tectum, in the optic nerve and in defined retinal cell populations, including retinal ganglion cells (RGCs). Furthermore, Mmp14a loss-of-function results in perturbed retinoblast cell cycle kinetics and consequently, in a delayed retinal neurogenesis, differentiation and lamination. These Mmp14a-dependent retinal defects lead to microphthalmia and a significantly reduced innervation of the optic tectum (OT) by RGC axons. Mmp14b, on the contrary, does not appear to alter retinal neurogenesis or OT innervation. As mammalian MMP14 is known to act as an efficient MMP2-activator, we also explored and found a functional link and a possible co-involvement of Mmp2 and Mmp14a in zebrafish retinotectal development. Conclusion Both the Mmp14a expression in the developing visual system and the Mmp14a loss-of-function phenotype illustrate a critical role for Mmp14a activity in retinal and retinotectal development.
Telomerase Is Required for Zebrafish Lifespan  [PDF]
Catarina M. Henriques,Madalena C. Carneiro,Inês M. Tenente,António Jacinto,Miguel Godinho Ferreira
PLOS Genetics , 2013, DOI: 10.1371/journal.pgen.1003214
Abstract: Telomerase activity is restricted in humans. Consequentially, telomeres shorten in most cells throughout our lives. Telomere dysfunction in vertebrates has been primarily studied in inbred mice strains with very long telomeres that fail to deplete telomeric repeats during their lifetime. It is, therefore, unclear how telomere shortening regulates tissue homeostasis in vertebrates with naturally short telomeres. Zebrafish have restricted telomerase expression and human-like telomere length. Here we show that first-generation tert?/? zebrafish die prematurely with shorter telomeres. tert?/? fish develop degenerative phenotypes, including premature infertility, gastrointestinal atrophy, and sarcopaenia. tert?/? mutants have impaired cell proliferation, accumulation of DNA damage markers, and a p53 response leading to early apoptosis, followed by accumulation of senescent cells. Apoptosis is primarily observed in the proliferative niche and germ cells. Cell proliferation, but not apoptosis, is rescued in tp53?/?tert?/? mutants, underscoring p53 as mediator of telomerase deficiency and consequent telomere instability. Thus, telomerase is limiting for zebrafish lifespan, enabling the study of telomere shortening in naturally ageing individuals.
Isabelle Aerts, Livia Lumbroso-Le Rouic, Marion Gauthier-Villars, Hervé Brisse, Fran?ois Doz, Laurence Desjardins
Orphanet Journal of Rare Diseases , 2006, DOI: 10.1186/1750-1172-1-31
Abstract: Retinoblastoma.Retinoblastoma is a rare eye tumor of childhood that arises in the retina and represents the most common intraocular malignancy of infancy and childhood [1]. It may occur at any age but most often it occurs in younger children, usually before the age of two years.The incidence is 1 in 15,000–20,000 live births. In 60% of cases, the disease is unilateral and the median age at diagnosis is two years. Of these cases, 15% are hereditary. Retinoblastoma is bilateral in about 40% of cases with a median age at diagnosis of one year. All bilateral and multifocal unilateral forms are hereditary.Leukocoria (white reflection in the pupil) and strabismus are the most frequent clinical manifestations of retinoblastoma (Figure 1). Leukocoria is initially inconstant, visible only at certain angles and under certain light conditions. This sign may be seen on flash photography. Strabismus, when present, becomes rapidly constant, reflecting impairment of the vision. These signs are still all-too-often overlooked and justify an ophthalmological consultation with ocular fundus examination. Some other signs may be observed, including iris rubeosis, hypopyon, hyphema, buphthalmia, orbital cellulitis, and exophthalmia. Some children with retinoblastoma may have no symptoms. Screening in case of familial history or dysmorphic syndrome with a 13q14 deletion [2] may lead to diagnosis of retinoblastoma. Most affected children are diagnosed before the age of five years.Retinoblastoma is the first disease for which a genetic etiology of cancer has been described and the first tumor suppressor gene identified. Knudson in 1971 developed the hypothesis that retinoblastoma is a cancer caused by two mutational events [3]. This led to the understanding that there are two forms of retinoblastoma, germinal and non germinal. Loss or mutations of both alleles of the retinoblastoma gene RB1, localized to chromosome 13q1.4 [4], are required to develop the disease. In hereditary cases (repres
Cell Size Checkpoint Control by the Retinoblastoma Tumor Suppressor Pathway  [PDF]
Su-Chiung Fang,Chris de los Reyes,James G Umen
PLOS Genetics , 2006, DOI: 10.1371/journal.pgen.0020167
Abstract: Size control is essential for all proliferating cells, and is thought to be regulated by checkpoints that couple cell size to cell cycle progression. The aberrant cell-size phenotypes caused by mutations in the retinoblastoma (RB) tumor suppressor pathway are consistent with a role in size checkpoint control, but indirect effects on size caused by altered cell cycle kinetics are difficult to rule out. The multiple fission cell cycle of the unicellular alga Chlamydomonas reinhardtii uncouples growth from division, allowing direct assessment of the relationship between size phenotypes and checkpoint function. Mutations in the C. reinhardtii RB homolog encoded by MAT3 cause supernumerous cell divisions and small cells, suggesting a role for MAT3 in size control. We identified suppressors of an mat3 null allele that had recessive mutations in DP1 or dominant mutations in E2F1, loci encoding homologs of a heterodimeric transcription factor that is targeted by RB-related proteins. Significantly, we determined that the dp1 and e2f1 phenotypes were caused by defects in size checkpoint control and were not due to a lengthened cell cycle. Despite their cell division defects, mat3, dp1, and e2f1 mutants showed almost no changes in periodic transcription of genes induced during S phase and mitosis, many of which are conserved targets of the RB pathway. Conversely, we found that regulation of cell size was unaffected when S phase and mitotic transcription were inhibited. Our data provide direct evidence that the RB pathway mediates cell size checkpoint control and suggest that such control is not directly coupled to the magnitude of periodic cell cycle transcription.
The Retinoblastoma Tumor Suppressor Regulates a Xenobiotic Detoxification Pathway  [PDF]
Maria Teresa Sáenz Robles, Ashley Case, Jean-Leon Chong, Gustavo Leone, James M. Pipas
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0026019
Abstract: The retinoblastoma tumor suppressor (pRb) regulates cell cycle entry, progression and exit by controlling the activity of the E2F-family of transcription factors. During cell cycle exit pRb acts as a transcriptional repressor by associating with E2F proteins and thereby inhibiting their ability to stimulate the expression of genes required for S phase. Indeed, many tumors harbor mutations in the RB gene and the pRb-E2F pathway is compromised in nearly all types of cancers. In this report we show that both pRb and its interacting partners, the transcriptional factors E2F1-2-3, act as positive modulators of detoxification pathways important for metabolizing and clearing xenobiotics—such as toxins and drugs—from the body. Using a combination of conventional molecular biology techniques and microarray analysis of specific cell populations, we have analyzed the detoxification pathway in murine samples in the presence or absence of pRb and/or E2F1-2-3. In this report, we show that both pRb and E2F1-2-3 act as positive modulators of detoxification pathways in mice, challenging the conventional view of E2F1-2-3 as transcriptional repressors negatively regulated by pRb. These results suggest that mutations altering the pRb-E2F axis may have consequences beyond loss of cell cycle control by altering the ability of tissues to remove toxins and to properly metabolize anticancer drugs, and might help to understand the formation and progression rates of different types of cancer, as well as to better design appropriate therapies based on the particular genetic composition of the tumors.
Structure-function analysis of the retinoblastoma tumor suppressor protein – is the whole a sum of its parts?
Frederick A Dick
Cell Division , 2007, DOI: 10.1186/1747-1028-2-26
Abstract: The retinoblastoma susceptibility gene (RB-1) was the first tumor suppressor gene to be cloned [1]. Since that time its encoded protein (pRB) has emerged as a key regulator of cell cycle entry and appears to be one of the most frequent targets for inactivation in human cancer [2-5]. The retinoblastoma protein is most frequently inactivated in cancer by the negative regulatory activity of cyclin dependent kinases [6]. Only in small cell lung carcinoma [7] and retinoblastoma [8] is the RB-1 gene a frequent target for direct mutation. Loss of heterozygosity at the RB-1 locus has been reported in many different sporadic cancers, suggesting that it is directly mutated outside of the lung and retina, but on a less frequent basis [9]. Based on pRB's prominent and ubiquitous role in cancer many investigators have focused their efforts on trying to determine its biochemical function. A fundamental component to this type of investigation is the evaluation of mutant alleles to determine which aspects of cell physiology require pRB. Ideally the analysis of very specific mutants will determine which protein interactions account for how pRB functions. This review will focus on the efforts that have been made to rationally separate different aspects of pRB's function in proliferative control and cancer.Given that the focus of this review is on the dissection of pRB function, some reports will inevitably be omitted because they lack a structural component. By no means is this is meant to diminish their validity, it is hoped that all aspects of pRB function will eventually fit into a framework of defined protein interactions, unfortunately not all are at this stage. In general terms, pRB has an established role in mediating a G1 arrest in development and in response to many growth regulatory signals [5]. Some examples are DNA damage [10], or growth inhibiting cytokines such as TGF-β [11]. In addition, pRB plays a key role in the permanent cell cycle exit of differentiating cells and
Meis1 specifies positional information in the retina and tectum to organize the zebrafish visual system
Timothy Erickson, Curtis R French, Andrew J Waskiewicz
Neural Development , 2010, DOI: 10.1186/1749-8104-5-22
Abstract: meis1 is expressed in both the presumptive retina and tectum. An analysis of retinal patterning reveals that Meis1 is required to correctly specify both dorsal-ventral and nasal-temporal identity in the zebrafish retina. Meis1-knockdown results in a loss of smad1 expression and an upregulation in follistatin expression, thereby causing lower levels of Bmp signalling and a partial ventralization of the retina. Additionally, Meis1-deficient embryos exhibit ectopic Fgf signalling in the developing retina and a corresponding loss of temporal identity. Meis1 also positively regulates ephrin gene expression in the tectum. Consistent with these patterning phenotypes, a knockdown of Meis1 ultimately results in retinotectal mapping defects.In this work we describe a novel role for Meis1 in regulating Bmp signalling and in specifying temporal identity in the retina. By patterning both the retina and tectum, Meis1 plays an important role in establishing the retinotectal map and organizing the visual system.In order to preserve the spatial coordinates of visual input, retinal ganglion cell (RGC) axons are topographically organized in the visual processing centres of the midbrain. Retinotopic mapping has been most extensively studied in the optic tectum of fish, amphibians, and chick, and in the superior colliculus of mice. Within both the retina and the tectum, axially restricted expression of the Eph and Ephrin families of axon guidance molecules provides some of the positional information required for retinotectal map formation. Interactions between Eph receptor tyrosine kinases and their cognate Ephrin ligands result in cytoskeletal rearrangements and changes in cell adhesion, thereby eliciting either repulsive or attractive responses. By interpreting the molecular Eph and Ephrin code, RGC axons form a precisely ordered arrangement within the optic tectum that accurately reflects their axial position within the retina [1,2].Axial patterning of the retina is required to estab
Wnt Signaling Is Required for Early Development of Zebrafish Swimbladder  [PDF]
Ao Yin,Svitlana Korzh,Cecilia L. Winata,Vladimir Korzh,Zhiyuan Gong
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0018431
Abstract: Wnt signaling plays critical roles in mammalian lung development. However, Wnt signaling in the development of the zebrafish swimbladder, which is considered as a counterpart of mammalian lungs, have not been explored. To investigate the potential conservation of signaling events in early development of the lung and swimbladder, we wish to address the question whether Wnt signaling plays a role in swimbladder development.
The functional loss of the retinoblastoma tumour suppressor is a common event in basal-like and luminal B breast carcinomas
Jason I Herschkowitz, Xiaping He, Cheng Fan, Charles M Perou
Breast Cancer Research , 2008, DOI: 10.1186/bcr2142
Abstract: We used gene expression analysis for tumour subtyping and polymorphic markers located at the RB1 locus to assess the frequency of loss of heterozygosity in 88 primary human breast carcinomas and their normal tissue genomic DNA samples.RB1 loss of heterozygosity was observed at an overall frequency of 39%, with a high frequency in basal-like (72%) and luminal B (62%) tumours. These tumours also concurrently showed low expression of RB1 mRNA. p16INK4a was highly expressed in basal-like tumours, presumably due to a previously reported feedback loop caused by RB1 loss. An RB1 loss of heterozygosity signature was developed and shown to be highly prognostic, and was potentially a predictive marker of response to neoadjuvant chemotherapy.These results suggest that the functional loss of RB1 is common in basal-like tumours, which may play a key role in dictating their aggressive biology and unique therapeutic responses.The retinoblastoma tumour suppressor gene (RB1) encodes a nuclear phosphoprotein that plays a central role in regulating the cell cycle [1]. Inactivation of both alleles of this gene is involved in the development of retinoblastoma, which is a rare childhood malignancy. The loss of RB1 is also a well-characterised occurrence in many other human tumour types and it is probable that the p16INK4a-CDK4/6-RB pathway is disrupted in most human tumours [2]. RB1 regulates progression through the G1 to S-phase transition of the cell cycle. In cells entering the cell cycle, extracellular signals induce the expression of D-type cyclins, which bind to and activate cyclin-dependent kinases (CDK4 and CDK6); these complexes in turn lead to the phosphorylation of RB and its dissociation from E2F family members that then transcriptionally activate many genes required for the S phase [1]. The INK4 family of CDK inhibitors (p16INK4a, p15INK4b, p18INK4c and p19INK4d) inhibits CDK4 and CDK6, retaining RB in its hypo-phosphorylated E2F-associated state, thereby preventing G1 to S-
Mediator Subunit 12 Is Required for Neutrophil Development in Zebrafish  [PDF]
Maria-Cristina Keightley, Judith E. Layton, John W. Hayman, Joan K. Heath, Graham J. Lieschke
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0023845
Abstract: Hematopoiesis requires the spatiotemporal organization of regulatory factors to successfully orchestrate diverse lineage specificity from stem and progenitor cells. Med12 is a regulatory component of the large Mediator complex that enables contact between the general RNA polymerase II transcriptional machinery and enhancer bound regulatory factors. We have identified a new zebrafish med12 allele, syr, with a single missense mutation causing a valine to aspartic acid change at position 1046. Syr shows defects in hematopoiesis, which predominantly affect the myeloid lineage. Syr has identified a hematopoietic cell-specific requirement for Med12, suggesting a new role for this transcriptional regulator.
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