The hedgehog (Hh) signaling pathway plays fundamental roles during embryonic development and tumo... more The hedgehog (Hh) signaling pathway plays fundamental roles during embryonic development and tumorigenesis. Previously, we have shown that ablation of the tumor suppressor and negative regulator, Suppressor of fused (Sufu), within this pathway causes embryonic lethality around E9.5 in the mouse. Here, we examine how lack of Sufu influences early cell fate determination processes. We established embryonic stem cell (ESC) lines from pre-implantation Sufu-/- and wild-type mouse embryos and show that these ESCs express the typical pluripotency markers, alkaline phosphatase, SSEA-1, Oct4, Sox2, and Nanog. We demonstrate that these ESCs express all core Hh pathway components, and that Gli1 mRNA levels are increased in Sufu-/- ESCs. Upon spontaneous differentiation of Sufu-/- ESCs, into embryoid bodies (EBs) in vitro, the Hh pathway is strongly upregulated as indicated by an increase in both Gli1 and Ptch1 gene expression. Interestingly, developing Sufu-/- EBs were smaller than their wild-type counterparts and showed decreased expression of the ectodermal markers Fgf5 and Sox1. In vivo teratoma formation revealed that Sufu-/- ESCs have a limited capacity for differentiation as the resulting tumors lacked the mesodermal derivatives cartilage and bone. However, Sufu-/- ESCs were able to develop into chondrocytes and osteocytes in vitro, which suggests a differential response of ESCs compared to in vivo conditions. Our findings suggest a regulatory function of the Hh signaling pathway in early mesodermal cell fate determination and emphasize the role of Sufu as a key molecule in this process.
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, Jan 15, 2015
Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disorder that is most commo... more Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disorder that is most commonly caused by a de novo point mutation in exon 11 of the LMNA gene, c.1824C>T, which results in an increased production of a truncated form of lamin A known as progerin. In this study, we used a mouse model to study the possibility of recovering from HGPS bone disease upon silencing of the HGPS mutation, and the potential benefits from treatment with resveratrol. We show that complete silencing of the transgenic expression of progerin normalized bone morphology and mineralization already after 7 weeks. The improvements included lower frequencies of rib fractures and callus formation, an increased number of osteocytes in remodeled bone, and normalized dentinogenesis. The beneficial effects from resveratrol treatment were less significant and to a large extent similar to mice treated with sucrose alone. However, the reversal of the dental phenotype of overgrown and laterally displaced l...
Candida albicans is a commensal organism that lives as benign member of the microflora of healthy... more Candida albicans is a commensal organism that lives as benign member of the microflora of healthy individuals. In response to changes in the host immune status or microflora, C. albicans ceases to be a commensal organism and infects a variety of host tissues. The capacity to shift from a commensal to pathogenic state requires a coordinated metabolic response that triggers discrete developmental programs and that induce the expression of specific virulence traits. Several virulence traits have been described in C. albicans including adhesion, morphological and phenotypic switching, and the production of secreted hydrolytic enzymes. These attributes contribute to host tissue recognition, tissue invasion and colonization, as well as evasion of the host immune response. Recent experimental progress has illuminated some of the cellular processes that enable Candida cells to sense and respond to changes in the host environment. Similarly, cells of the host innate immune system are able to...
Pathbase (http://www.pathbase.net) is a web accessible database of histopathological images of la... more Pathbase (http://www.pathbase.net) is a web accessible database of histopathological images of laboratory mice, developed as a resource for the coding and archiving of data derived from the analysis of mutant or genetically engineered mice and their background strains. The metadata for the images, which allows retrieval and interoperability with other databases, is derived from a series of orthogonal ontologies and controlled vocabularies. One of these controlled vocabularies, MPATH, was developed by the Pathbase Consortium as a formal description of the content of mouse histopathological images. The database currently has over 1000 images on-line with 2000 more under curation and presents a paradigm for the development of future databases dedicated to aspects of experimental biology.
... Paul N Schofield 1 , Steve DM Brown 2 , John P Sundberg 3 , Mark Arends 4 , Madhuri V Warren ... more ... Paul N Schofield 1 , Steve DM Brown 2 , John P Sundberg 3 , Mark Arends 4 , Madhuri V Warren 5, 6 , Pierre Dubus 7 , Michele Ellender 8 , Laurence Fiette 9 , Bjorn Rozell 10 , Leticia Quintanilla-Martinez 11 , Marcello Raspa 12 , Ji-Ying Song 13 , Martin van ... Ingrid Sundberg. ...
Dysregulation of the Hedgehog signaling pathway is central to the development of certain tumor ty... more Dysregulation of the Hedgehog signaling pathway is central to the development of certain tumor types, including medulloblastoma and basal cell carcinoma (BCC). Patched1 (Ptch1) and Suppressor of fused (Sufu) are two essential negative regulators of the pathway with tumor suppressor activity. Ptch1(+/-) mice are predisposed to developing medulloblastoma and rhabdomyosarcoma, while Sufu(+/-) mice develop a skin phenotype characterized by basaloid epidermal proliferations. Here, we have studied tumor development in Sufu(+/-)Ptch1(+/-) mice to determine the effect of compound heterozygosity on the onset, incidence, and spectrum of tumors. We found significantly more (2.3-fold) basaloid proliferations in Sufu(+/-)Ptch1(+/-) compared to Sufu(+/-) female, but not male, mice. For medulloblastoma, the cumulative 1-yr incidence was 1.5-fold higher in Sufu(+/-)Ptch1(+/-) compared to Ptch1(+/-) female mice but this strong trend was not statistically significant. Together this suggests a weak genetic interaction of the two tumor suppressor genes. We noted a few rhabdomyosarcomas and pancreatic cysts in the Sufu(+/-)Ptch1(+/-) mice, but the numbers were not significantly different from the single heterozygous mice. Hydrocephalus developed in approximately 20% of the Ptch1(+/-) and Sufu(+/-)Ptch1(+/-) but not in Sufu(+/-) mice. Interestingly, most of the medulloblastomas from the Sufu(+/-)Ptch1(+/-) mice had lost expression of the remaining Ptch1 wild-type allele but not the Sufu wild-type allele. On the contrary, Sufu as well as Gli1 and Gli2 expression was upregulated in the medulloblastomas compared to adult cerebellum in Ptch1(+/-) and Sufu(+/-)Ptch1(+/-) mice. This suggests that Sufu expression may be regulated by Hedgehog pathway activity and could constitute another negative feedback loop in the pathway.
Krüppel-like factor5 (Klf5) is a zinc-finger transcription factor normally expressed in the skin.... more Krüppel-like factor5 (Klf5) is a zinc-finger transcription factor normally expressed in the skin. Here, we show that overexpression of Klf5 in the basal layer of the epidermis during embryogenesis affects epidermal development and disrupts epithelial-mesenchymal interactions necessary for skin adnexae formation as well as craniofacial morphogenesis. The transgenic mice exhibited exencephaly, craniofacial defects, persistent abdominal herniation and ectodermal dysplasia. Moreover, the epidermis was hypoplastic and underwent abnormal differentiation with expression of keratin8, a marker for single-layered epithelia, in the stratified epidermis. Correspondingly, we observed a downregulation of DeltaNp63 expression in the skin. Overexpression of Klf5 in adult mice led to hyperkeratosis, follicle occlusion and epidermal erosions. Further, we observed decrease and even loss of the stem cell population of bulge keratinocytes, as characterized by the expression pattern of alpha6 integrin and CD34 markers. Our data suggest a new role of Klf5 as a modulator of p63 expression and the differentiation program of epidermal cells relevant for regenerative potential of the epidermis and epithelial-mesenchymal interactions.
The European Radiobiology Archives (ERA), together with corresponding Japanese and American datab... more The European Radiobiology Archives (ERA), together with corresponding Japanese and American databases, hold data from nearly all experimental animal radiation biology studies carried out between 1960 and 1998, involving more than 300,000 animals. The Federal Office for Radiation Protection, together with the University of Cambridge have undertaken to transfer the existing ERA archive to a web-based database to maximize its usefulness to the scientific community and bring data coding and structure of this legacy database into congruence with currently accepted semantic standards for anatomy and pathology. The accuracy of the primary data input was assessed and improved. The original rodent pathology nomenclature was recoded to replace the local 'DIS-ROD' (Disease Rodent) formalism with Mouse Pathology (MPATH) and Mouse Anatomy (MA) ontology terms. A pathology panel sampled histopathological slide material and compared the original diagnoses with currently accepted diagnostic criteria. The overall non-systematic error rate varied among the studies between 0.26% and 4.41%, the mean error being 1.71%. The errors found have been corrected and the studies thus controlled have been annotated. The majority of the original pathology terms have been successfully translated into a combination of MPATH and MA ontology terms. ERA has the potential of becoming a world-wide radiobiological research tool for numerous applications, such as the re-analysis of existing data with new approaches in the light of new hypotheses and techniques, and using the database as an information resource for planning future animal studies. When the database is opened for new data it may be possible to offer long-term storage of data from recent and future animal studies.
The hedgehog (Hh) signaling pathway plays fundamental roles during embryonic development and tumo... more The hedgehog (Hh) signaling pathway plays fundamental roles during embryonic development and tumorigenesis. Previously, we have shown that ablation of the tumor suppressor and negative regulator, Suppressor of fused (Sufu), within this pathway causes embryonic lethality around E9.5 in the mouse. Here, we examine how lack of Sufu influences early cell fate determination processes. We established embryonic stem cell (ESC) lines from pre-implantation Sufu-/- and wild-type mouse embryos and show that these ESCs express the typical pluripotency markers, alkaline phosphatase, SSEA-1, Oct4, Sox2, and Nanog. We demonstrate that these ESCs express all core Hh pathway components, and that Gli1 mRNA levels are increased in Sufu-/- ESCs. Upon spontaneous differentiation of Sufu-/- ESCs, into embryoid bodies (EBs) in vitro, the Hh pathway is strongly upregulated as indicated by an increase in both Gli1 and Ptch1 gene expression. Interestingly, developing Sufu-/- EBs were smaller than their wild-type counterparts and showed decreased expression of the ectodermal markers Fgf5 and Sox1. In vivo teratoma formation revealed that Sufu-/- ESCs have a limited capacity for differentiation as the resulting tumors lacked the mesodermal derivatives cartilage and bone. However, Sufu-/- ESCs were able to develop into chondrocytes and osteocytes in vitro, which suggests a differential response of ESCs compared to in vivo conditions. Our findings suggest a regulatory function of the Hh signaling pathway in early mesodermal cell fate determination and emphasize the role of Sufu as a key molecule in this process.
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, Jan 15, 2015
Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disorder that is most commo... more Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disorder that is most commonly caused by a de novo point mutation in exon 11 of the LMNA gene, c.1824C>T, which results in an increased production of a truncated form of lamin A known as progerin. In this study, we used a mouse model to study the possibility of recovering from HGPS bone disease upon silencing of the HGPS mutation, and the potential benefits from treatment with resveratrol. We show that complete silencing of the transgenic expression of progerin normalized bone morphology and mineralization already after 7 weeks. The improvements included lower frequencies of rib fractures and callus formation, an increased number of osteocytes in remodeled bone, and normalized dentinogenesis. The beneficial effects from resveratrol treatment were less significant and to a large extent similar to mice treated with sucrose alone. However, the reversal of the dental phenotype of overgrown and laterally displaced l...
Candida albicans is a commensal organism that lives as benign member of the microflora of healthy... more Candida albicans is a commensal organism that lives as benign member of the microflora of healthy individuals. In response to changes in the host immune status or microflora, C. albicans ceases to be a commensal organism and infects a variety of host tissues. The capacity to shift from a commensal to pathogenic state requires a coordinated metabolic response that triggers discrete developmental programs and that induce the expression of specific virulence traits. Several virulence traits have been described in C. albicans including adhesion, morphological and phenotypic switching, and the production of secreted hydrolytic enzymes. These attributes contribute to host tissue recognition, tissue invasion and colonization, as well as evasion of the host immune response. Recent experimental progress has illuminated some of the cellular processes that enable Candida cells to sense and respond to changes in the host environment. Similarly, cells of the host innate immune system are able to...
Pathbase (http://www.pathbase.net) is a web accessible database of histopathological images of la... more Pathbase (http://www.pathbase.net) is a web accessible database of histopathological images of laboratory mice, developed as a resource for the coding and archiving of data derived from the analysis of mutant or genetically engineered mice and their background strains. The metadata for the images, which allows retrieval and interoperability with other databases, is derived from a series of orthogonal ontologies and controlled vocabularies. One of these controlled vocabularies, MPATH, was developed by the Pathbase Consortium as a formal description of the content of mouse histopathological images. The database currently has over 1000 images on-line with 2000 more under curation and presents a paradigm for the development of future databases dedicated to aspects of experimental biology.
... Paul N Schofield 1 , Steve DM Brown 2 , John P Sundberg 3 , Mark Arends 4 , Madhuri V Warren ... more ... Paul N Schofield 1 , Steve DM Brown 2 , John P Sundberg 3 , Mark Arends 4 , Madhuri V Warren 5, 6 , Pierre Dubus 7 , Michele Ellender 8 , Laurence Fiette 9 , Bjorn Rozell 10 , Leticia Quintanilla-Martinez 11 , Marcello Raspa 12 , Ji-Ying Song 13 , Martin van ... Ingrid Sundberg. ...
Dysregulation of the Hedgehog signaling pathway is central to the development of certain tumor ty... more Dysregulation of the Hedgehog signaling pathway is central to the development of certain tumor types, including medulloblastoma and basal cell carcinoma (BCC). Patched1 (Ptch1) and Suppressor of fused (Sufu) are two essential negative regulators of the pathway with tumor suppressor activity. Ptch1(+/-) mice are predisposed to developing medulloblastoma and rhabdomyosarcoma, while Sufu(+/-) mice develop a skin phenotype characterized by basaloid epidermal proliferations. Here, we have studied tumor development in Sufu(+/-)Ptch1(+/-) mice to determine the effect of compound heterozygosity on the onset, incidence, and spectrum of tumors. We found significantly more (2.3-fold) basaloid proliferations in Sufu(+/-)Ptch1(+/-) compared to Sufu(+/-) female, but not male, mice. For medulloblastoma, the cumulative 1-yr incidence was 1.5-fold higher in Sufu(+/-)Ptch1(+/-) compared to Ptch1(+/-) female mice but this strong trend was not statistically significant. Together this suggests a weak genetic interaction of the two tumor suppressor genes. We noted a few rhabdomyosarcomas and pancreatic cysts in the Sufu(+/-)Ptch1(+/-) mice, but the numbers were not significantly different from the single heterozygous mice. Hydrocephalus developed in approximately 20% of the Ptch1(+/-) and Sufu(+/-)Ptch1(+/-) but not in Sufu(+/-) mice. Interestingly, most of the medulloblastomas from the Sufu(+/-)Ptch1(+/-) mice had lost expression of the remaining Ptch1 wild-type allele but not the Sufu wild-type allele. On the contrary, Sufu as well as Gli1 and Gli2 expression was upregulated in the medulloblastomas compared to adult cerebellum in Ptch1(+/-) and Sufu(+/-)Ptch1(+/-) mice. This suggests that Sufu expression may be regulated by Hedgehog pathway activity and could constitute another negative feedback loop in the pathway.
Krüppel-like factor5 (Klf5) is a zinc-finger transcription factor normally expressed in the skin.... more Krüppel-like factor5 (Klf5) is a zinc-finger transcription factor normally expressed in the skin. Here, we show that overexpression of Klf5 in the basal layer of the epidermis during embryogenesis affects epidermal development and disrupts epithelial-mesenchymal interactions necessary for skin adnexae formation as well as craniofacial morphogenesis. The transgenic mice exhibited exencephaly, craniofacial defects, persistent abdominal herniation and ectodermal dysplasia. Moreover, the epidermis was hypoplastic and underwent abnormal differentiation with expression of keratin8, a marker for single-layered epithelia, in the stratified epidermis. Correspondingly, we observed a downregulation of DeltaNp63 expression in the skin. Overexpression of Klf5 in adult mice led to hyperkeratosis, follicle occlusion and epidermal erosions. Further, we observed decrease and even loss of the stem cell population of bulge keratinocytes, as characterized by the expression pattern of alpha6 integrin and CD34 markers. Our data suggest a new role of Klf5 as a modulator of p63 expression and the differentiation program of epidermal cells relevant for regenerative potential of the epidermis and epithelial-mesenchymal interactions.
The European Radiobiology Archives (ERA), together with corresponding Japanese and American datab... more The European Radiobiology Archives (ERA), together with corresponding Japanese and American databases, hold data from nearly all experimental animal radiation biology studies carried out between 1960 and 1998, involving more than 300,000 animals. The Federal Office for Radiation Protection, together with the University of Cambridge have undertaken to transfer the existing ERA archive to a web-based database to maximize its usefulness to the scientific community and bring data coding and structure of this legacy database into congruence with currently accepted semantic standards for anatomy and pathology. The accuracy of the primary data input was assessed and improved. The original rodent pathology nomenclature was recoded to replace the local 'DIS-ROD' (Disease Rodent) formalism with Mouse Pathology (MPATH) and Mouse Anatomy (MA) ontology terms. A pathology panel sampled histopathological slide material and compared the original diagnoses with currently accepted diagnostic criteria. The overall non-systematic error rate varied among the studies between 0.26% and 4.41%, the mean error being 1.71%. The errors found have been corrected and the studies thus controlled have been annotated. The majority of the original pathology terms have been successfully translated into a combination of MPATH and MA ontology terms. ERA has the potential of becoming a world-wide radiobiological research tool for numerous applications, such as the re-analysis of existing data with new approaches in the light of new hypotheses and techniques, and using the database as an information resource for planning future animal studies. When the database is opened for new data it may be possible to offer long-term storage of data from recent and future animal studies.
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Papers by Björn Rozell