Matthias Schäfer - Academia.edu (original) (raw)

Papers by Matthias Schäfer

Journal of Investigative Dermatology, 2018

Tretinoin, also known as all-trans retinoic acid (ATRA), is well-known for its anti-aging effects... more Tretinoin, also known as all-trans retinoic acid (ATRA), is well-known for its anti-aging effects on skin. However, skin irritation, photochemical instability, and concerns about toxicity have hindered the use of ATRA in cosmetic products. Therefore, it is desirable to find new molecules that have increased retinoic acidlike activity without the negative side effects. Hydroxypinacolone retinoate (HPR) is a cosmetic grade ester of ATRA that has been shown to have innate retinoic acid activity without causing skin irritation. Here, we compared levels of gene transcription by HPR, ATRA, retinol (ROL), retinaldehyde (RAL), and retinyl palmitate (RP) in DNA using a retinoic acid response element (RARE) reporter assay. In addition, we compared the anti-aging properties of HPR to ATRA by testing the effects on collagen levels and skin irritation in organotypic skin models. Skin models were treated for 5 days with HPR and ATRA, basal media was collected for ELISA analysis, and skins were stained with Massons trichrome (for collagen). RARE assay results showed that HPR had greater levels of gene transcription than ROL, RAL, and RP at the same concentrations, and was less cytotoxic to cells at a 10 times higher concentration; however, HPR did not achieve gene transcription levels of ATRA. Skins treated with HPR significantly increased pro-collagen production as compared with untreated control skins, and was comparable to ATRA. Histological staining of skins for collagen corroborated these results, with the highest dose of HPR out-performing ATRA. IL-1a ELISA analysis showed that HPR did not induce more (or less) inflammatory response than either ATRA or the vehicle control. Together these data suggest that HPR is an effective alternative to ATRA and other less potent retinoids in the treatment of aging skin without the detrimental side effects.

Journal of Investigative Dermatology, 2017

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare genetic skin disease caused by loss o... more Recessive dystrophic epidermolysis bullosa (RDEB) is a rare genetic skin disease caused by loss of function mutations in the gene encoding type VII collagen (COL7A1). RDEB is characterized by trauma induced wounds and excessive scarring, and one of the most frequent complications in RDEB is the development of fatal squamous cell carcinoma (SCC). Our published and unpublished data show that TGF-beta signaling is increased in RDEB, and others have shown that TGF-beta is a major disease modifier. We previously demonstrated that the matricellular protein thrombospondin-1 (TSP1) is increased in RDEB fibroblasts and that COL7A1 expression modulates TSP1. Here we investigated the role of TSP1 in TGF-beta activation in RDEB primary fibroblasts. Knock-down of TSP1 reduced phosphorylation of SMAD3 (a downstream target of TGF-beta signaling) in RDEB patient fibroblasts, but not in non-RDEB normal breast fibroblasts. Over-expression of COL7A1 in RDEB fibroblasts reduced intracellular TSP1 and phosphorylated SMAD3. Furthermore, peptide inhibition of TSP1 binding to the TGF-beta e latency associated protein complex decreased nuclear localization of phosphorylated SMAD3 in tissue engineered extracellular matrix (ECM) from RDEB fibroblasts compared with controls and to a similar extent as observed after SB-431542 inhibition of the TGF-beta type I receptor. Decreased nuclear phosphorylated SMAD3 correlated with a decrease in collagen fiber formation in tissue engineered ECM from RDEB fibroblasts treated with the peptide TSP1 inhibitor, as evaluated by picrosirius red staining followed by analyses of birefringent collagen fibrillar deposits using a polarizing microscope. These data suggest TSP1 is a major activator of TGF-beta signaling in RDEB and identify TSP1 as a potent therapeutic target.

The American Journal of Pathology, 2018

Journal of Investigative Dermatology, 2017

Although the epidermal growth factor receptor has established roles in skin carcinogenesis, infla... more Although the epidermal growth factor receptor has established roles in skin carcinogenesis, inflammation, and wound healing, the functions of the structurally related receptor ERBB2 in this tissue remain poorly explored. To assess the functions of ERBB2 in skin homeostasis, tumorigenesis, and wound healing, we employed keratin 5-directed, cre recombinase-mediated targeting of Erbb2 alleles in mice. Erbb2 del mice, lacking ERBB2 specifically in keratinocytes, showed no noticeable spontaneous skin abnormalities. During early wound healing, the thickness and the number and proliferation rate of keratinocytes in the wound epithelium of Erbb2 del mice were significantly reduced. Compared with control littermates, Erbb2 del mice remained free of papillomas for a longer time and had significantly reduced tumor burden after application of the 7,12-dimethylbenz[a]anthracene/12-O-tetradecanoylphorbol-13-acetate multistage chemical carcinogenesis protocol. Furthermore, tumor cell proliferation was substantially reduced in Erbb2 del mice, and loss of ERBB2 also decreased keratinocyte proliferation after 12-O-tetradecanoylphorbol-13-acetate application. Thus, ERBB2 is dispensable for the development and homeostasis of the epidermis and its appendages. However, reflecting its pro-proliferative role, ERBB2 is required for the normal healing of skin wounds and for the progression of tumors during skin chemical carcinogenesis in mice. Thus, ERBB2 may be a promising target for inhibiting human nonmelanoma skin cancer progression.

The Journal of investigative dermatology, Feb 1, 2016

The in situ control of redox insult in human organs is of major clinical relevance, yet remains i... more The in situ control of redox insult in human organs is of major clinical relevance, yet remains incompletely understood. Activation of Nrf2, the "master regulator" of genes controlling cellular redox homeostasis, is advocated as a therapeutic strategy for diseases with severely impaired redox balance. It remains to be shown whether this strategy is effective in human organs, rather than isolated human cell types. We have therefore explored the role of Nrf2 in a uniquely accessible human (mini-) organ, human scalp hair follicles (HFs). Microarray and qPCR analysis of human HFs following Nrf2 activation using sulforaphane identified the modulation of phase II metabolism, ROS clearance, the pentose phosphate pathway and glutathione homeostasis. Nrf2 knockdown (siRNA) in cultured human HFs confirmed the regulation of key Nrf2 target genes (i.e. HO-1, NQO1, GSR, GCLC, ABCC1, PRDX1). Importantly, Nrf2 activation significantly reduced ROS levels and associated lipid peroxidation....

European Journal of Cell Biology, Aug 3, 2006

Cancer research, Jan 3, 2015

Pharmacologic activation of the transcription factor NRF2 has been suggested to offer a strategy ... more Pharmacologic activation of the transcription factor NRF2 has been suggested to offer a strategy for cancer prevention. In this study, we present evidence from murine tumorigenesis experiments suggesting there may be limitations to this possibility, based on tumorigenic effects of Nrf2 in murine keratinocytes that have not been described previously. In this setting, Nrf2 expression conferred metabolic alterations in keratinocytes that were protumorigenic in nature, affecting enzymes involved in glutathione biosynthesis or in the oxidative pentose phosphate pathway and other NADPH-producing enzymes. Under stress conditions, coordinate increases in NADPH, purine, and glutathione levels promoted the survival of keratinocytes harboring oncogenic mutations, thereby promoting tumor development. The protumorigenic activity of Nrf2 in keratinocytes was particularly significant in a mouse model of skin tumorigenesis that did not rely upon chemical carcinogenesis. In exploring the clinical re...

Molecular Oncology, 2015

The epidermal growth factor receptor (EGFR) plays a key role in skin inflammation, wound healing,... more The epidermal growth factor receptor (EGFR) plays a key role in skin inflammation, wound healing, and carcinogenesis. Less is known about the functions of the structurally related receptor ERBB3 (HER3) in the skin. We assessed the requirement of ERBB3 for skin homeostasis, wound healing, and tumorigenesis by crossing mice carrying a conditional Erbb3 allele with animals expressing cre under the control of the keratin 5 promoter. Erbb3del mice, lacking ERBB3 specifically in keratinocytes, showed no obvious abnormalities. The EGFR was upregulated in Erbb3del skin, possibly compensating the loss of ERBB3. Nonetheless, healing of full‐thickness excisional wounds was negatively affected by ERBB3 deficiency. To analyze the function of ERBB3 during tumorigenesis, we employed the established DMBA/TPA multi‐stage chemical carcinogenesis protocol. Erbb3del mice remained free of papillomas for a longer time and had significantly reduced tumor burden compared to control littermates. Tumor cell ...

Molecular and cellular biology, 2014

The epidermal growth factor receptor (EGFR) system is a key regulator of epithelial development a... more The epidermal growth factor receptor (EGFR) system is a key regulator of epithelial development and homeostasis. Its functions in the sebaceous gland (SG), however, remain poorly characterized. In this study, using a transgenic mouse line with tissue-specific and inducible expression of the EGFR ligand epigen, we showed that increased activation of the EGFR in skin keratinocytes results in enlarged SGs and increased sebum production. The phenotype can be reverted by interrupting transgene expression and is EGFR dependent, as gland size and sebum levels return to normal values after crossing to the EGFR-impaired mouse line Wa5. Intriguingly, however, the SG enlargement appears only if EGFR activation occurs before birth. Importantly, the enlarged sebaceous glands are associated with an increased expression of the transcription factor MYC and of the transmembrane proteins LRIG1, an established negative-feedback regulator of the EGFR/ERBB tyrosine kinase receptors and a stem cell marke...

Nature Communications, 2014

PLoS ONE, 2013

The nuclear factor erythroid 2-related factor 2 (Nrf2) governs the expression of antioxidant and ... more The nuclear factor erythroid 2-related factor 2 (Nrf2) governs the expression of antioxidant and phase II detoxifying enzymes. Nrf2 activation can prevent or reduce cellular damage associated with several types of injury in many different tissues and organs. Dominant mutations in Cu/Zn-superoxide dismutase (SOD1) cause familial forms of amyotrophic lateral sclerosis (ALS), a fatal disorder characterized by the progressive loss of motor neurons and subsequent muscular atrophy. We have previously shown that Nrf2 activation in astrocytes delays neurodegeneration in ALS mouse models. To further investigate the role of Nrf2 in ALS we determined the effect of absence of Nrf2 or its restricted overexpression in neurons or type II skeletal muscle fibers on symptoms onset and survival in mutant hSOD1 expressing mice. We did not observe any detrimental effect associated with the lack of Nrf2 in two different mutant hSOD1 animal models of ALS. However, restricted Nrf2 overexpression in neurons or type II skeletal muscle fibers delayed disease onset but failed to extend survival in hSOD1 G93A mice. These results highlight the concept that not only the pharmacological target but also the cell type targeted may be relevant when considering a Nrf2-mediated therapeutic approach for ALS.

Nucleic Acids Research, 2014

Journal of Clinical Investigation, 2012

Genome Research, 2003

In mammals, the unique midkine (mdk) gene encodes a secreted heparin-binding growth factor with n... more In mammals, the unique midkine (mdk) gene encodes a secreted heparin-binding growth factor with neurotrophic activity. Here, we show the presence of two functional mdk genes named mdka and mdkb in zebrafish and rainbow trout. Both midkine proteins are clearly different from the related pleiotrophin, which was also identified in zebrafish and other fishes. Zebrafish mdka and mdkb genes map to linkage groups LG7 and LG25, respectively, both presenting synteny to human chromosome 11, in which the unique human ortholog mdk is located. At least four other genes unique in mammals are also present as duplicates on LG7 and LG25. Phylogenetic and divergence analyses suggested that LG7/LG25 paralogs including mdka and mdkb have been formed at approximately the same time, early during the evolution of the fish lineage. Hence, zebrafish and rainbow trout mdka and mdkb might have been generated by an ancient block duplication, and might be remnants of the proposed fish-specific whole-genome dupl...

Genes & Development, 2005

The medial floor plate (MFP) organizes the specification of neurons and outgrowth of axons in the... more The medial floor plate (MFP) organizes the specification of neurons and outgrowth of axons in the ventral spinal cord of vertebrates. We show that the growth factor Midkine-a, expressed in the paraxial mesoderm, is required for formation of the MFP in zebrafish. Our epistatic analyses demonstrate that development of MFP comprises two independent sequential phases. Following initial MFP induction in the gastrula organizer, Midkine-a regulates allocation of MFP cells during subsequent development. Thus in zebrafish, trunk-derived signals are required for complete MFP formation from a common pool of organizer-derived midline precursor cells.

American Journal of Physiology-Gastrointestinal and Liver Physiology, 2012

Mutations in the main intestinal and kidney luminal neutral amino acid transporter B0AT1 (Slc6a19... more Mutations in the main intestinal and kidney luminal neutral amino acid transporter B0AT1 (Slc6a19) lead to Hartnup disorder, a condition that is characterized by neutral aminoaciduria and in some cases pellagra-like symptoms. These latter symptoms caused by low-niacin are thought to result from defective intestinal absorption of its precursor l-tryptophan. Since Ace2 is necessary for intestinal B0AT1 expression, we tested the impact of intestinal B0AT1 absence in ace2 null mice. Their weight gain following weaning was decreased, and Na+-dependent uptake of B0AT1 substrates measured in everted intestinal rings was defective. Additionally, high-affinity Na+-dependent transport of l-proline, presumably via SIT1 (Slc6a20), was absent, whereas glucose uptake via SGLT1 (Slc5a1) was not affected. Measurements of small intestine luminal amino acid content following gavage showed that more l-tryptophan than other B0AT1 substrates reach the ileum in wild-type mice, which is in line with its k...

Cell death and differentiation, Jan 27, 2018

The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is a key regulator of... more The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is a key regulator of the cellular stress response, but the biological functions of the related Nrf3 protein are largely unknown. Here we demonstrate a novel pro-apoptotic function of Nrf3 in mouse and human keratinocytes. In response to UV irradiation, Nrf3-deficient keratinocytes were protected from apoptosis in vitro and in vivo. The protective function was also seen under oxidative or hyperosmotic stress conditions, but not when apoptosis was induced by disruption of cell-matrix interactions. Mechanistically, we show that Nrf3-deficient keratinocytes exhibit stronger cell-cell and cell-matrix adhesion, which correlates with higher cell surface integrin levels and enhanced activation of focal adhesion kinase. Nrf3-deficient cells also formed more and larger focal adhesions and exhibited a higher motility. These results suggest that the strong expression of Nrf3 in basal keratinocytes promotes their elimin...

Cancer Research, 2013

The antioxidant enzyme peroxiredoxin 6 (Prdx6) is a key regulator of the cellular redox balance, ... more The antioxidant enzyme peroxiredoxin 6 (Prdx6) is a key regulator of the cellular redox balance, particularly under stress conditions. We identified Prdx6 as an important player in different phases of skin carcinogenesis. Loss of Prdx6 in mice enhanced the susceptibility to skin tumorigenesis, whereas overexpression of Prdx6 in keratinocytes of transgenic mice had the opposite effect. The tumor-preventive effect of Prdx6, which was observed in a human papilloma virus 8–induced and a chemically induced tumor model, was not due to alterations in keratinocyte proliferation, apoptosis, or in the inflammatory response. Rather, endogenous and overexpressed Prdx6 reduced oxidative stress as reflected by the lower levels of oxidized phospholipids in the protumorigenic skin of Prdx6 transgenic mice and the higher levels in Prdx6-knockout mice than in control animals. In contrast to its beneficial effect in tumor prevention, overexpression of Prdx6 led to an acceleration of malignant progress...

Journal of Investigative Dermatology, 2018

Tretinoin, also known as all-trans retinoic acid (ATRA), is well-known for its anti-aging effects... more Tretinoin, also known as all-trans retinoic acid (ATRA), is well-known for its anti-aging effects on skin. However, skin irritation, photochemical instability, and concerns about toxicity have hindered the use of ATRA in cosmetic products. Therefore, it is desirable to find new molecules that have increased retinoic acidlike activity without the negative side effects. Hydroxypinacolone retinoate (HPR) is a cosmetic grade ester of ATRA that has been shown to have innate retinoic acid activity without causing skin irritation. Here, we compared levels of gene transcription by HPR, ATRA, retinol (ROL), retinaldehyde (RAL), and retinyl palmitate (RP) in DNA using a retinoic acid response element (RARE) reporter assay. In addition, we compared the anti-aging properties of HPR to ATRA by testing the effects on collagen levels and skin irritation in organotypic skin models. Skin models were treated for 5 days with HPR and ATRA, basal media was collected for ELISA analysis, and skins were stained with Massons trichrome (for collagen). RARE assay results showed that HPR had greater levels of gene transcription than ROL, RAL, and RP at the same concentrations, and was less cytotoxic to cells at a 10 times higher concentration; however, HPR did not achieve gene transcription levels of ATRA. Skins treated with HPR significantly increased pro-collagen production as compared with untreated control skins, and was comparable to ATRA. Histological staining of skins for collagen corroborated these results, with the highest dose of HPR out-performing ATRA. IL-1a ELISA analysis showed that HPR did not induce more (or less) inflammatory response than either ATRA or the vehicle control. Together these data suggest that HPR is an effective alternative to ATRA and other less potent retinoids in the treatment of aging skin without the detrimental side effects.

Journal of Investigative Dermatology, 2017

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare genetic skin disease caused by loss o... more Recessive dystrophic epidermolysis bullosa (RDEB) is a rare genetic skin disease caused by loss of function mutations in the gene encoding type VII collagen (COL7A1). RDEB is characterized by trauma induced wounds and excessive scarring, and one of the most frequent complications in RDEB is the development of fatal squamous cell carcinoma (SCC). Our published and unpublished data show that TGF-beta signaling is increased in RDEB, and others have shown that TGF-beta is a major disease modifier. We previously demonstrated that the matricellular protein thrombospondin-1 (TSP1) is increased in RDEB fibroblasts and that COL7A1 expression modulates TSP1. Here we investigated the role of TSP1 in TGF-beta activation in RDEB primary fibroblasts. Knock-down of TSP1 reduced phosphorylation of SMAD3 (a downstream target of TGF-beta signaling) in RDEB patient fibroblasts, but not in non-RDEB normal breast fibroblasts. Over-expression of COL7A1 in RDEB fibroblasts reduced intracellular TSP1 and phosphorylated SMAD3. Furthermore, peptide inhibition of TSP1 binding to the TGF-beta e latency associated protein complex decreased nuclear localization of phosphorylated SMAD3 in tissue engineered extracellular matrix (ECM) from RDEB fibroblasts compared with controls and to a similar extent as observed after SB-431542 inhibition of the TGF-beta type I receptor. Decreased nuclear phosphorylated SMAD3 correlated with a decrease in collagen fiber formation in tissue engineered ECM from RDEB fibroblasts treated with the peptide TSP1 inhibitor, as evaluated by picrosirius red staining followed by analyses of birefringent collagen fibrillar deposits using a polarizing microscope. These data suggest TSP1 is a major activator of TGF-beta signaling in RDEB and identify TSP1 as a potent therapeutic target.

The American Journal of Pathology, 2018

Journal of Investigative Dermatology, 2017

Although the epidermal growth factor receptor has established roles in skin carcinogenesis, infla... more Although the epidermal growth factor receptor has established roles in skin carcinogenesis, inflammation, and wound healing, the functions of the structurally related receptor ERBB2 in this tissue remain poorly explored. To assess the functions of ERBB2 in skin homeostasis, tumorigenesis, and wound healing, we employed keratin 5-directed, cre recombinase-mediated targeting of Erbb2 alleles in mice. Erbb2 del mice, lacking ERBB2 specifically in keratinocytes, showed no noticeable spontaneous skin abnormalities. During early wound healing, the thickness and the number and proliferation rate of keratinocytes in the wound epithelium of Erbb2 del mice were significantly reduced. Compared with control littermates, Erbb2 del mice remained free of papillomas for a longer time and had significantly reduced tumor burden after application of the 7,12-dimethylbenz[a]anthracene/12-O-tetradecanoylphorbol-13-acetate multistage chemical carcinogenesis protocol. Furthermore, tumor cell proliferation was substantially reduced in Erbb2 del mice, and loss of ERBB2 also decreased keratinocyte proliferation after 12-O-tetradecanoylphorbol-13-acetate application. Thus, ERBB2 is dispensable for the development and homeostasis of the epidermis and its appendages. However, reflecting its pro-proliferative role, ERBB2 is required for the normal healing of skin wounds and for the progression of tumors during skin chemical carcinogenesis in mice. Thus, ERBB2 may be a promising target for inhibiting human nonmelanoma skin cancer progression.

The Journal of investigative dermatology, Feb 1, 2016

The in situ control of redox insult in human organs is of major clinical relevance, yet remains i... more The in situ control of redox insult in human organs is of major clinical relevance, yet remains incompletely understood. Activation of Nrf2, the "master regulator" of genes controlling cellular redox homeostasis, is advocated as a therapeutic strategy for diseases with severely impaired redox balance. It remains to be shown whether this strategy is effective in human organs, rather than isolated human cell types. We have therefore explored the role of Nrf2 in a uniquely accessible human (mini-) organ, human scalp hair follicles (HFs). Microarray and qPCR analysis of human HFs following Nrf2 activation using sulforaphane identified the modulation of phase II metabolism, ROS clearance, the pentose phosphate pathway and glutathione homeostasis. Nrf2 knockdown (siRNA) in cultured human HFs confirmed the regulation of key Nrf2 target genes (i.e. HO-1, NQO1, GSR, GCLC, ABCC1, PRDX1). Importantly, Nrf2 activation significantly reduced ROS levels and associated lipid peroxidation....

European Journal of Cell Biology, Aug 3, 2006

Cancer research, Jan 3, 2015

Pharmacologic activation of the transcription factor NRF2 has been suggested to offer a strategy ... more Pharmacologic activation of the transcription factor NRF2 has been suggested to offer a strategy for cancer prevention. In this study, we present evidence from murine tumorigenesis experiments suggesting there may be limitations to this possibility, based on tumorigenic effects of Nrf2 in murine keratinocytes that have not been described previously. In this setting, Nrf2 expression conferred metabolic alterations in keratinocytes that were protumorigenic in nature, affecting enzymes involved in glutathione biosynthesis or in the oxidative pentose phosphate pathway and other NADPH-producing enzymes. Under stress conditions, coordinate increases in NADPH, purine, and glutathione levels promoted the survival of keratinocytes harboring oncogenic mutations, thereby promoting tumor development. The protumorigenic activity of Nrf2 in keratinocytes was particularly significant in a mouse model of skin tumorigenesis that did not rely upon chemical carcinogenesis. In exploring the clinical re...

Molecular Oncology, 2015

The epidermal growth factor receptor (EGFR) plays a key role in skin inflammation, wound healing,... more The epidermal growth factor receptor (EGFR) plays a key role in skin inflammation, wound healing, and carcinogenesis. Less is known about the functions of the structurally related receptor ERBB3 (HER3) in the skin. We assessed the requirement of ERBB3 for skin homeostasis, wound healing, and tumorigenesis by crossing mice carrying a conditional Erbb3 allele with animals expressing cre under the control of the keratin 5 promoter. Erbb3del mice, lacking ERBB3 specifically in keratinocytes, showed no obvious abnormalities. The EGFR was upregulated in Erbb3del skin, possibly compensating the loss of ERBB3. Nonetheless, healing of full‐thickness excisional wounds was negatively affected by ERBB3 deficiency. To analyze the function of ERBB3 during tumorigenesis, we employed the established DMBA/TPA multi‐stage chemical carcinogenesis protocol. Erbb3del mice remained free of papillomas for a longer time and had significantly reduced tumor burden compared to control littermates. Tumor cell ...

Molecular and cellular biology, 2014

The epidermal growth factor receptor (EGFR) system is a key regulator of epithelial development a... more The epidermal growth factor receptor (EGFR) system is a key regulator of epithelial development and homeostasis. Its functions in the sebaceous gland (SG), however, remain poorly characterized. In this study, using a transgenic mouse line with tissue-specific and inducible expression of the EGFR ligand epigen, we showed that increased activation of the EGFR in skin keratinocytes results in enlarged SGs and increased sebum production. The phenotype can be reverted by interrupting transgene expression and is EGFR dependent, as gland size and sebum levels return to normal values after crossing to the EGFR-impaired mouse line Wa5. Intriguingly, however, the SG enlargement appears only if EGFR activation occurs before birth. Importantly, the enlarged sebaceous glands are associated with an increased expression of the transcription factor MYC and of the transmembrane proteins LRIG1, an established negative-feedback regulator of the EGFR/ERBB tyrosine kinase receptors and a stem cell marke...

Nature Communications, 2014

PLoS ONE, 2013

The nuclear factor erythroid 2-related factor 2 (Nrf2) governs the expression of antioxidant and ... more The nuclear factor erythroid 2-related factor 2 (Nrf2) governs the expression of antioxidant and phase II detoxifying enzymes. Nrf2 activation can prevent or reduce cellular damage associated with several types of injury in many different tissues and organs. Dominant mutations in Cu/Zn-superoxide dismutase (SOD1) cause familial forms of amyotrophic lateral sclerosis (ALS), a fatal disorder characterized by the progressive loss of motor neurons and subsequent muscular atrophy. We have previously shown that Nrf2 activation in astrocytes delays neurodegeneration in ALS mouse models. To further investigate the role of Nrf2 in ALS we determined the effect of absence of Nrf2 or its restricted overexpression in neurons or type II skeletal muscle fibers on symptoms onset and survival in mutant hSOD1 expressing mice. We did not observe any detrimental effect associated with the lack of Nrf2 in two different mutant hSOD1 animal models of ALS. However, restricted Nrf2 overexpression in neurons or type II skeletal muscle fibers delayed disease onset but failed to extend survival in hSOD1 G93A mice. These results highlight the concept that not only the pharmacological target but also the cell type targeted may be relevant when considering a Nrf2-mediated therapeutic approach for ALS.

Nucleic Acids Research, 2014

Journal of Clinical Investigation, 2012

Genome Research, 2003

In mammals, the unique midkine (mdk) gene encodes a secreted heparin-binding growth factor with n... more In mammals, the unique midkine (mdk) gene encodes a secreted heparin-binding growth factor with neurotrophic activity. Here, we show the presence of two functional mdk genes named mdka and mdkb in zebrafish and rainbow trout. Both midkine proteins are clearly different from the related pleiotrophin, which was also identified in zebrafish and other fishes. Zebrafish mdka and mdkb genes map to linkage groups LG7 and LG25, respectively, both presenting synteny to human chromosome 11, in which the unique human ortholog mdk is located. At least four other genes unique in mammals are also present as duplicates on LG7 and LG25. Phylogenetic and divergence analyses suggested that LG7/LG25 paralogs including mdka and mdkb have been formed at approximately the same time, early during the evolution of the fish lineage. Hence, zebrafish and rainbow trout mdka and mdkb might have been generated by an ancient block duplication, and might be remnants of the proposed fish-specific whole-genome dupl...

Genes & Development, 2005

The medial floor plate (MFP) organizes the specification of neurons and outgrowth of axons in the... more The medial floor plate (MFP) organizes the specification of neurons and outgrowth of axons in the ventral spinal cord of vertebrates. We show that the growth factor Midkine-a, expressed in the paraxial mesoderm, is required for formation of the MFP in zebrafish. Our epistatic analyses demonstrate that development of MFP comprises two independent sequential phases. Following initial MFP induction in the gastrula organizer, Midkine-a regulates allocation of MFP cells during subsequent development. Thus in zebrafish, trunk-derived signals are required for complete MFP formation from a common pool of organizer-derived midline precursor cells.

American Journal of Physiology-Gastrointestinal and Liver Physiology, 2012

Mutations in the main intestinal and kidney luminal neutral amino acid transporter B0AT1 (Slc6a19... more Mutations in the main intestinal and kidney luminal neutral amino acid transporter B0AT1 (Slc6a19) lead to Hartnup disorder, a condition that is characterized by neutral aminoaciduria and in some cases pellagra-like symptoms. These latter symptoms caused by low-niacin are thought to result from defective intestinal absorption of its precursor l-tryptophan. Since Ace2 is necessary for intestinal B0AT1 expression, we tested the impact of intestinal B0AT1 absence in ace2 null mice. Their weight gain following weaning was decreased, and Na+-dependent uptake of B0AT1 substrates measured in everted intestinal rings was defective. Additionally, high-affinity Na+-dependent transport of l-proline, presumably via SIT1 (Slc6a20), was absent, whereas glucose uptake via SGLT1 (Slc5a1) was not affected. Measurements of small intestine luminal amino acid content following gavage showed that more l-tryptophan than other B0AT1 substrates reach the ileum in wild-type mice, which is in line with its k...

Cell death and differentiation, Jan 27, 2018

The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is a key regulator of... more The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is a key regulator of the cellular stress response, but the biological functions of the related Nrf3 protein are largely unknown. Here we demonstrate a novel pro-apoptotic function of Nrf3 in mouse and human keratinocytes. In response to UV irradiation, Nrf3-deficient keratinocytes were protected from apoptosis in vitro and in vivo. The protective function was also seen under oxidative or hyperosmotic stress conditions, but not when apoptosis was induced by disruption of cell-matrix interactions. Mechanistically, we show that Nrf3-deficient keratinocytes exhibit stronger cell-cell and cell-matrix adhesion, which correlates with higher cell surface integrin levels and enhanced activation of focal adhesion kinase. Nrf3-deficient cells also formed more and larger focal adhesions and exhibited a higher motility. These results suggest that the strong expression of Nrf3 in basal keratinocytes promotes their elimin...

Cancer Research, 2013

The antioxidant enzyme peroxiredoxin 6 (Prdx6) is a key regulator of the cellular redox balance, ... more The antioxidant enzyme peroxiredoxin 6 (Prdx6) is a key regulator of the cellular redox balance, particularly under stress conditions. We identified Prdx6 as an important player in different phases of skin carcinogenesis. Loss of Prdx6 in mice enhanced the susceptibility to skin tumorigenesis, whereas overexpression of Prdx6 in keratinocytes of transgenic mice had the opposite effect. The tumor-preventive effect of Prdx6, which was observed in a human papilloma virus 8–induced and a chemically induced tumor model, was not due to alterations in keratinocyte proliferation, apoptosis, or in the inflammatory response. Rather, endogenous and overexpressed Prdx6 reduced oxidative stress as reflected by the lower levels of oxidized phospholipids in the protumorigenic skin of Prdx6 transgenic mice and the higher levels in Prdx6-knockout mice than in control animals. In contrast to its beneficial effect in tumor prevention, overexpression of Prdx6 led to an acceleration of malignant progress...