doris herzlinger - Academia.edu (original) (raw)
Papers by doris herzlinger
Seminars in cell & developmental biology, 2014
The renal vascular bed has a stereotypic architecture that is essential for the kidney's role... more The renal vascular bed has a stereotypic architecture that is essential for the kidney's role in excreting metabolic waste and regulating the volume and composition of body fluids. The kidney's excretory functions are dependent on the delivery of the majority of renal blood flow to the glomerular capillaries, which filter plasma removing from it metabolic waste, as well as vast quantities of solutes and fluids. The renal tubules reabsorb from the glomerular filtrate solutes and fluids required for homeostasis, while the post-glomerular capillary beds return these essential substances back into the systemic circulation. Thus, the kidney's regulatory functions are dependent on the close proximity or alignment of the post-glomerular capillary beds with the renal tubules. This review will focus on our current knowledge of the mechanisms controlling the embryonic development of the renal vasculature. An understanding of this process is critical for developing novel therapies ...
American Journal of Physiology-Renal Physiology
Kidney development requires reciprocal interactions between the ureteric bud and the metanephroge... more Kidney development requires reciprocal interactions between the ureteric bud and the metanephrogenic mesenchyme. Whereas survival of mesenchyme and development of nephrons from mesenchymal cells depends on signals from the invading ureteric bud, growth of the ureteric bud depends on signals from the mesenchyme. This codependency makes it difficult to identify molecules expressed by the ureteric bud that regulate mesenchymal growth. To determine how the ureteric bud signals the mesenchyme, we previously isolated ureteric bud cell lines (UB cells). These cells secrete soluble factors which rescue the mesenchyme from apoptosis. We now report that four heparin binding factors mediate this growth activity. One of these is basic fibroblast growth factor (bFGF), which is synthesized by the ureteric bud when penetrating the mesenchyme. bFGF rescues three types of progenitors found in the mesenchyme: precursors of tubular epithelia, precursors of capillaries, and cells that regulate growth o...
Angiogenesis
The principal function of glomeruli is to filter blood through a highly specialized filtration ba... more The principal function of glomeruli is to filter blood through a highly specialized filtration barrier consisting of a fenestrated endothelium, the glomerular basement membrane and podocyte foot processes. Previous studies have uncovered a crucial role of endothelial a disintegrin and metalloprotease 10 (ADAM10) and Notch signaling in the development of glomeruli, yet the resulting defects have not been further characterized nor understood in the context of kidney development. Here, we used several different experimental approaches to analyze the kidneys and glomeruli from mice lacking ADAM10 in endothelial cells (A10ΔEC mice). Scanning electron microscopy of glomerular casts demonstrated enlarged vascular diameter and increased intussusceptive events in A10ΔEC glomeruli compared to controls. Consistent with these findings, genes known to regulate vessel caliber (Apln, AplnR and Vegfr3) are significantly upregulated in A10ΔEC glomeruli. Moreover, transmission electron microscopy revealed the persistence of diaphragms in the fenestrae of A10ΔEC glomerular endothelial cells, which was corroborated by the elevated expression of the protein PLVAP/PV-1, an integral component of fenestral diaphragms. Analysis of gross renal vasculature by light sheet microscopy showed no major alteration of the branching pattern, indicating a localized importance of ADAM10 in the glomerular endothelium. Since intussusceptions and fenestrae with diaphragms are normally found in developing, but not mature glomeruli, our results provide the first evidence for a crucial role of endothelial ADAM10, a key regulator of Notch signaling, in promoting the development and maturation of the glomerular vasculature.
Journal of neurosurgery, Jan 13, 2016
OBJECTIVE Delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage (aSAH) occ... more OBJECTIVE Delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage (aSAH) occurs in approximately 30% of patients. The Practical Risk Chart was developed to predict DCI based on admission characteristics; the authors seek to externally validate and critically appraise this prediction tool. METHODS A prospective cohort of aSAH patients was used to externally validate the previously published Practical Risk Chart. The model consists of 4 variables: clinical condition on admission, amount of cisternal and intraventricular blood on CT, and age. External validity was assessed using logistic regression. Model discrimination was evaluated using the area under the receiver operating characteristic curve (AUC). RESULTS In a cohort of 125 patients with aSAH, the Practical Risk Chart adequately predicted DCI, with an AUC of 0.66 (95% CI 0.55-0.77). Clinical grade on admission and amount of intracranial blood on CT were the strongest predictors of DCI and clinical vasospasm....
Seminars in Nephrology, Aug 1, 1995
The conversion of intermediate mesoderm into renal tubular structures occurs throughout embryonic... more The conversion of intermediate mesoderm into renal tubular structures occurs throughout embryonic development from the formation of the nephric duct through to the generation of metanephric nephrons. Studies using an in vitro model system of renal epithelial morphogenesis indicate that the signals mediating tubulogenesis rescue intermediate mesoderm from programmed cell death, trigger spindle-shaped mesodermal cells to differentiate into epithelia, and lastly promote epithelial cell diversification and segmented tubule assembly. Recent data indicate that members of the Wnt family of developmental regulatory genes play an important role in the signaling pathway mediating renal epithelial morphogenesis.
Society of General Physiologists series, 1988
The American journal of physiology, 1992
We have derived an immortalized cell line from primary cultures of bicarbonate-secreting intercal... more We have derived an immortalized cell line from primary cultures of bicarbonate-secreting intercalated cells from rabbit. Cells were transfected with a plasmid encoding a temperature-sensitive large T antigen of SV40 plus the neomycin resistance gene under the control of an SV40 promoter. Transfectants were selected for resistance to G418. One stably transfected clone, designated IC250, was subcloned to ensure clonality, and a subclone (clone C) was characterized in detail. The cells divide continuously at permissive temperature. At restrictive temperature, they cease dividing and assume morphological and transport properties of true bicarbonate-secreting intercalated cells. They express appropriate ultrastructural features, bind peanut lectin in an apical pattern, are rich in carbonic anhydrase, stain for proton-adenosinetriphosphatase in a basolateral pattern, and do not stain with antibodies to erythrocyte band 3. Most monolayers of transformed type B intercalated cells do not ach...
The Journal of Cell Biology, 1992
During metanephric development, non-polarized mesenchymal cells are induced to form the epithelia... more During metanephric development, non-polarized mesenchymal cells are induced to form the epithelial structures of the nephron following interaction with extracellular matrix proteins and factors produced by the inducing tissue, ureteric bud. This induction can occur in a transfilter organ culture system where it can also be produced by heterologous cells such as the embryonic spinal cord. We found that when embryonic mesenchyme was induced in vitro and in vivo, many of the cells surrounding the new epithelium showed morphological evidence of programmed cell death (apoptosis) such as condensed nuclei, fragmented cytoplasm, and cell shrinking. A biochemical correlate of apoptosis is the transcriptional activation of a calcium-sensitive endonuclease. Indeed, DNA isolated from uninduced mesenchyme showed progressive degradation, a process that was prevented by treatment with actinomycin-D or cycloheximide and by buffering intracellular calcium. These results demonstrate that the metaneph...
Proceedings of the National Academy of Sciences, 1984
A dodecapeptide corresponding to the carboxyl terminus of the lac carrier of Escherichia coli was... more A dodecapeptide corresponding to the carboxyl terminus of the lac carrier of Escherichia coli was synthesized, coupled to thyroglobulin, and the conjugate was used to generate site-directed polyclonal antibodies. The antibodies react with the carboxyl-terminal peptide and with the lac carrier protein, while monoclonal antibody 4B1 reacts with intact lac carrier protein, but not with the carboxyl-terminal peptide. Antibody 4B1 binds preferentially to right-side-out membrane vesicles relative to inside-out vesicles, confirming the presence of the 4B1 epitope on the periplasmic surface of the membrane. Alternatively, anti-carboxyl-terminal antibody binds preferentially to inside-out vesicles, demonstrating that the carboxyl terminus of the lac carrier protein is on the cytoplasmic surface. Surprisingly, both antibodies bind to proteoliposomes reconstituted with purified lac carrier protein, and quantitative binding assays indicate that the epitopes are equally accessible. When proteoli...
The Journal of Urology, 2008
The Journal of Urology, 1999
![Research paper thumbnail of Corrigendum to “A high-resolution anatomical ontology of the developing murine genitourinary tract” [Gene Expression Patterns 7 (2007) 680–699]](https://attachments.academia-assets.com/83471219/thumbnails/1.jpg)
](Gene Expression Patterns, 2007
Developmental Dynamics, 2004
Developmental Biology, 1994
Developmental Biology, 2009
Development, 2005
During kidney morphogenesis, the formation of nephrons begins when mesenchymal nephron progenitor... more During kidney morphogenesis, the formation of nephrons begins when mesenchymal nephron progenitor cells aggregate and transform into epithelial vesicles that elongate and assume an S-shape. Cells in different regions of the S-shaped body subsequently differentiate into the morphologically and functionally distinct segments of the mature nephron. Here, we have used an allelic series of mutations to determine the role of the secreted signaling molecule FGF8 in nephrogenesis. In the absence of FGF8 signaling, nephron formation is initiated, but the nascent nephrons do not express Wnt4or Lim1, and nephrogenesis does not progress to the S-shaped body stage. Furthermore, the nephron progenitor cells that reside in the peripheral zone, the outermost region of the developing kidney, are progressively lost. When FGF8 signaling is severely reduced rather than eliminated, mesenchymal cells differentiate into S-shaped bodies. However, the cells within these structures that normally differentiat...
Developmental …, 1994
During kidney development, unknown signals derived from the ureteric bud induce metanephric mesen... more During kidney development, unknown signals derived from the ureteric bud induce metanephric mesenchymal cells to differentiate into nephron epithelia. In addition to the ureteric bud, a number of other tissues can act as heterologous inducers of this process in vitro, including ...
…, 2001
The Notch signaling pathway is an evolutionarily conserved intercellular signaling mechanism, and... more The Notch signaling pathway is an evolutionarily conserved intercellular signaling mechanism, and mutations in its components disrupt cell-fate specification and embryonic development in organisms as diverse as insects, sea urchins, nematodes and mammals. Genes of the ...
Annual Review of Physiology, 1994
... Page 10. 680 HERZLINGER a. b. c. nephric duct nephrogenic cora • mesonephric tubules Figure 3... more ... Page 10. 680 HERZLINGER a. b. c. nephric duct nephrogenic cora • mesonephric tubules Figure 3 Data supporting the contention that the epithelia of mesonephric tubules are exclusively derived from the nephrogenic cord are inconclusive. ...
Seminars in cell & developmental biology, 2014
The renal vascular bed has a stereotypic architecture that is essential for the kidney's role... more The renal vascular bed has a stereotypic architecture that is essential for the kidney's role in excreting metabolic waste and regulating the volume and composition of body fluids. The kidney's excretory functions are dependent on the delivery of the majority of renal blood flow to the glomerular capillaries, which filter plasma removing from it metabolic waste, as well as vast quantities of solutes and fluids. The renal tubules reabsorb from the glomerular filtrate solutes and fluids required for homeostasis, while the post-glomerular capillary beds return these essential substances back into the systemic circulation. Thus, the kidney's regulatory functions are dependent on the close proximity or alignment of the post-glomerular capillary beds with the renal tubules. This review will focus on our current knowledge of the mechanisms controlling the embryonic development of the renal vasculature. An understanding of this process is critical for developing novel therapies ...
American Journal of Physiology-Renal Physiology
Kidney development requires reciprocal interactions between the ureteric bud and the metanephroge... more Kidney development requires reciprocal interactions between the ureteric bud and the metanephrogenic mesenchyme. Whereas survival of mesenchyme and development of nephrons from mesenchymal cells depends on signals from the invading ureteric bud, growth of the ureteric bud depends on signals from the mesenchyme. This codependency makes it difficult to identify molecules expressed by the ureteric bud that regulate mesenchymal growth. To determine how the ureteric bud signals the mesenchyme, we previously isolated ureteric bud cell lines (UB cells). These cells secrete soluble factors which rescue the mesenchyme from apoptosis. We now report that four heparin binding factors mediate this growth activity. One of these is basic fibroblast growth factor (bFGF), which is synthesized by the ureteric bud when penetrating the mesenchyme. bFGF rescues three types of progenitors found in the mesenchyme: precursors of tubular epithelia, precursors of capillaries, and cells that regulate growth o...
Angiogenesis
The principal function of glomeruli is to filter blood through a highly specialized filtration ba... more The principal function of glomeruli is to filter blood through a highly specialized filtration barrier consisting of a fenestrated endothelium, the glomerular basement membrane and podocyte foot processes. Previous studies have uncovered a crucial role of endothelial a disintegrin and metalloprotease 10 (ADAM10) and Notch signaling in the development of glomeruli, yet the resulting defects have not been further characterized nor understood in the context of kidney development. Here, we used several different experimental approaches to analyze the kidneys and glomeruli from mice lacking ADAM10 in endothelial cells (A10ΔEC mice). Scanning electron microscopy of glomerular casts demonstrated enlarged vascular diameter and increased intussusceptive events in A10ΔEC glomeruli compared to controls. Consistent with these findings, genes known to regulate vessel caliber (Apln, AplnR and Vegfr3) are significantly upregulated in A10ΔEC glomeruli. Moreover, transmission electron microscopy revealed the persistence of diaphragms in the fenestrae of A10ΔEC glomerular endothelial cells, which was corroborated by the elevated expression of the protein PLVAP/PV-1, an integral component of fenestral diaphragms. Analysis of gross renal vasculature by light sheet microscopy showed no major alteration of the branching pattern, indicating a localized importance of ADAM10 in the glomerular endothelium. Since intussusceptions and fenestrae with diaphragms are normally found in developing, but not mature glomeruli, our results provide the first evidence for a crucial role of endothelial ADAM10, a key regulator of Notch signaling, in promoting the development and maturation of the glomerular vasculature.
Journal of neurosurgery, Jan 13, 2016
OBJECTIVE Delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage (aSAH) occ... more OBJECTIVE Delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage (aSAH) occurs in approximately 30% of patients. The Practical Risk Chart was developed to predict DCI based on admission characteristics; the authors seek to externally validate and critically appraise this prediction tool. METHODS A prospective cohort of aSAH patients was used to externally validate the previously published Practical Risk Chart. The model consists of 4 variables: clinical condition on admission, amount of cisternal and intraventricular blood on CT, and age. External validity was assessed using logistic regression. Model discrimination was evaluated using the area under the receiver operating characteristic curve (AUC). RESULTS In a cohort of 125 patients with aSAH, the Practical Risk Chart adequately predicted DCI, with an AUC of 0.66 (95% CI 0.55-0.77). Clinical grade on admission and amount of intracranial blood on CT were the strongest predictors of DCI and clinical vasospasm....
Seminars in Nephrology, Aug 1, 1995
The conversion of intermediate mesoderm into renal tubular structures occurs throughout embryonic... more The conversion of intermediate mesoderm into renal tubular structures occurs throughout embryonic development from the formation of the nephric duct through to the generation of metanephric nephrons. Studies using an in vitro model system of renal epithelial morphogenesis indicate that the signals mediating tubulogenesis rescue intermediate mesoderm from programmed cell death, trigger spindle-shaped mesodermal cells to differentiate into epithelia, and lastly promote epithelial cell diversification and segmented tubule assembly. Recent data indicate that members of the Wnt family of developmental regulatory genes play an important role in the signaling pathway mediating renal epithelial morphogenesis.
Society of General Physiologists series, 1988
The American journal of physiology, 1992
We have derived an immortalized cell line from primary cultures of bicarbonate-secreting intercal... more We have derived an immortalized cell line from primary cultures of bicarbonate-secreting intercalated cells from rabbit. Cells were transfected with a plasmid encoding a temperature-sensitive large T antigen of SV40 plus the neomycin resistance gene under the control of an SV40 promoter. Transfectants were selected for resistance to G418. One stably transfected clone, designated IC250, was subcloned to ensure clonality, and a subclone (clone C) was characterized in detail. The cells divide continuously at permissive temperature. At restrictive temperature, they cease dividing and assume morphological and transport properties of true bicarbonate-secreting intercalated cells. They express appropriate ultrastructural features, bind peanut lectin in an apical pattern, are rich in carbonic anhydrase, stain for proton-adenosinetriphosphatase in a basolateral pattern, and do not stain with antibodies to erythrocyte band 3. Most monolayers of transformed type B intercalated cells do not ach...
The Journal of Cell Biology, 1992
During metanephric development, non-polarized mesenchymal cells are induced to form the epithelia... more During metanephric development, non-polarized mesenchymal cells are induced to form the epithelial structures of the nephron following interaction with extracellular matrix proteins and factors produced by the inducing tissue, ureteric bud. This induction can occur in a transfilter organ culture system where it can also be produced by heterologous cells such as the embryonic spinal cord. We found that when embryonic mesenchyme was induced in vitro and in vivo, many of the cells surrounding the new epithelium showed morphological evidence of programmed cell death (apoptosis) such as condensed nuclei, fragmented cytoplasm, and cell shrinking. A biochemical correlate of apoptosis is the transcriptional activation of a calcium-sensitive endonuclease. Indeed, DNA isolated from uninduced mesenchyme showed progressive degradation, a process that was prevented by treatment with actinomycin-D or cycloheximide and by buffering intracellular calcium. These results demonstrate that the metaneph...
Proceedings of the National Academy of Sciences, 1984
A dodecapeptide corresponding to the carboxyl terminus of the lac carrier of Escherichia coli was... more A dodecapeptide corresponding to the carboxyl terminus of the lac carrier of Escherichia coli was synthesized, coupled to thyroglobulin, and the conjugate was used to generate site-directed polyclonal antibodies. The antibodies react with the carboxyl-terminal peptide and with the lac carrier protein, while monoclonal antibody 4B1 reacts with intact lac carrier protein, but not with the carboxyl-terminal peptide. Antibody 4B1 binds preferentially to right-side-out membrane vesicles relative to inside-out vesicles, confirming the presence of the 4B1 epitope on the periplasmic surface of the membrane. Alternatively, anti-carboxyl-terminal antibody binds preferentially to inside-out vesicles, demonstrating that the carboxyl terminus of the lac carrier protein is on the cytoplasmic surface. Surprisingly, both antibodies bind to proteoliposomes reconstituted with purified lac carrier protein, and quantitative binding assays indicate that the epitopes are equally accessible. When proteoli...
The Journal of Urology, 2008
The Journal of Urology, 1999
Gene Expression Patterns, 2007
Developmental Dynamics, 2004
Developmental Biology, 1994
Developmental Biology, 2009
Development, 2005
During kidney morphogenesis, the formation of nephrons begins when mesenchymal nephron progenitor... more During kidney morphogenesis, the formation of nephrons begins when mesenchymal nephron progenitor cells aggregate and transform into epithelial vesicles that elongate and assume an S-shape. Cells in different regions of the S-shaped body subsequently differentiate into the morphologically and functionally distinct segments of the mature nephron. Here, we have used an allelic series of mutations to determine the role of the secreted signaling molecule FGF8 in nephrogenesis. In the absence of FGF8 signaling, nephron formation is initiated, but the nascent nephrons do not express Wnt4or Lim1, and nephrogenesis does not progress to the S-shaped body stage. Furthermore, the nephron progenitor cells that reside in the peripheral zone, the outermost region of the developing kidney, are progressively lost. When FGF8 signaling is severely reduced rather than eliminated, mesenchymal cells differentiate into S-shaped bodies. However, the cells within these structures that normally differentiat...
Developmental …, 1994
During kidney development, unknown signals derived from the ureteric bud induce metanephric mesen... more During kidney development, unknown signals derived from the ureteric bud induce metanephric mesenchymal cells to differentiate into nephron epithelia. In addition to the ureteric bud, a number of other tissues can act as heterologous inducers of this process in vitro, including ...
…, 2001
The Notch signaling pathway is an evolutionarily conserved intercellular signaling mechanism, and... more The Notch signaling pathway is an evolutionarily conserved intercellular signaling mechanism, and mutations in its components disrupt cell-fate specification and embryonic development in organisms as diverse as insects, sea urchins, nematodes and mammals. Genes of the ...
Annual Review of Physiology, 1994
... Page 10. 680 HERZLINGER a. b. c. nephric duct nephrogenic cora • mesonephric tubules Figure 3... more ... Page 10. 680 HERZLINGER a. b. c. nephric duct nephrogenic cora • mesonephric tubules Figure 3 Data supporting the contention that the epithelia of mesonephric tubules are exclusively derived from the nephrogenic cord are inconclusive. ...