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Thomas M. Schultheiss - One of the best experts on this subject based on the ideXlab platform.
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Fgfr2 is required for the expansion of the early adrenocortical primordium.
Molecular and cellular endocrinology, 2015Co-Authors: Regine Häfner, Thomas M. Schultheiss, Tobias Bohnenpoll, Carsten Rudat, Andreas KispertAbstract:Abstract The adrenal cortex is a critical steroidogenic endocrine tissue, generated at least in part from Intermediate Mesoderm of the anterior urogenital ridge. Previous work has pinpointed a minor role of the FGFR2IIIb isoform in expansion and differentiation of the fetal adrenal cortex in mice but did not address the complete role of FGFR2 and FGFR1 signaling in adrenocortical development. Here, we show that a Tbx18 cre line mediates specific recombination in the coelomic epithelium of the anterior urogenital ridge which gives rise by a delamination process to the adrenocortical primordium. Mice with conditional ( Tbx18 cre -mediated) deletion of all isoforms of Fgfr2 exhibited severely hypoplastic adrenal glands around birth. Cortical cells were dramatically reduced in number but showed steroidogenic differentiation and zonation. Neuroendocrine chromaffin cells were also reduced and formed a cell cluster adjacent to but not encapsulated by steroidogenic cells. Analysis of earlier time points revealed that the adrenocortical primordium was established in the Intermediate Mesoderm at E10.5 but that it failed to expand at subsequent stages. Our further experiments show that FGFR2 signaling acts as early as E11.5 to prevent apoptosis and enhance proliferation in adrenocortical progenitor cells. FGFR1 signaling does not contribute to early adrenocortical development. Our work suggests that FGFR2IIIb and IIIc isoforms largely act redundantly to promote expansion of the adrenocortical primordium.
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a role for vg1 nodal signaling in specification of the Intermediate Mesoderm
Development, 2013Co-Authors: Britannia M. Fleming, Richard G. James, Ronit Yelin, Thomas M. SchultheissAbstract:The Intermediate Mesoderm (IM) is the embryonic source of all kidney tissue in vertebrates. The factors that regulate the formation of the IM are not yet well understood. Through investigations in the chick embryo, the current study identifies and characterizes Vg1/Nodal signaling (henceforth referred to as ‘Nodal-like signaling’) as a novel regulator of IM formation. Excess Nodal-like signaling at gastrulation stages resulted in expansion of the IM at the expense of the adjacent paraxial Mesoderm, whereas inhibition of Nodal-like signaling caused repression of IM gene expression. IM formation was sensitive to levels of the Nodal-like pathway co-receptor Cripto and was inhibited by a truncated form of the secreted molecule cerberus, which specifically blocks Nodal, indicating that the observed effects are specific to the Nodal-like branch of the TGFβ signaling pathway. The IM-promoting effects of Nodal-like signaling were distinct from the known effects of this pathway on Mesoderm formation and left-right patterning, a finding that can be attributed to specific time windows for the activities of these Nodal-like functions. Finally, a link was observed between Nodal-like and BMP signaling in the induction of IM. Activation of IM genes by Nodal-like signaling required an active BMP signaling pathway, and Nodal-like signals induced phosphorylation of Smad1/5/8, which is normally associated with activation of BMP signaling pathways. We postulate that Nodal-like signaling regulates IM formation by modulating the IM-inducing effects of BMP signaling.
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A role for Vg1/Nodal signaling in specification of the Intermediate Mesoderm.
Development (Cambridge England), 2013Co-Authors: Britannia M. Fleming, Richard G. James, Ronit Yelin, Thomas M. SchultheissAbstract:The Intermediate Mesoderm (IM) is the embryonic source of all kidney tissue in vertebrates. The factors that regulate the formation of the IM are not yet well understood. Through investigations in the chick embryo, the current study identifies and characterizes Vg1/Nodal signaling (henceforth referred to as ‘Nodal-like signaling’) as a novel regulator of IM formation. Excess Nodal-like signaling at gastrulation stages resulted in expansion of the IM at the expense of the adjacent paraxial Mesoderm, whereas inhibition of Nodal-like signaling caused repression of IM gene expression. IM formation was sensitive to levels of the Nodal-like pathway co-receptor Cripto and was inhibited by a truncated form of the secreted molecule cerberus, which specifically blocks Nodal, indicating that the observed effects are specific to the Nodal-like branch of the TGFβ signaling pathway. The IM-promoting effects of Nodal-like signaling were distinct from the known effects of this pathway on Mesoderm formation and left-right patterning, a finding that can be attributed to specific time windows for the activities of these Nodal-like functions. Finally, a link was observed between Nodal-like and BMP signaling in the induction of IM. Activation of IM genes by Nodal-like signaling required an active BMP signaling pathway, and Nodal-like signals induced phosphorylation of Smad1/5/8, which is normally associated with activation of BMP signaling pathways. We postulate that Nodal-like signaling regulates IM formation by modulating the IM-inducing effects of BMP signaling.
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Bmp signaling promotes Intermediate Mesoderm gene expression in a dose-dependent, cell-autonomous and translation-dependent manner
Developmental biology, 2005Co-Authors: Richard G. James, Thomas M. SchultheissAbstract:The Intermediate Mesoderm lies between the somites and the lateral plate and is the source of all kidney tissue in the developing vertebrate embryo. While bone morphogenetic protein (Bmp) signaling is known to regulate Mesodermal cell type determination along the medio-lateral axis, its role in Intermediate Mesoderm formation has not been well characterized. The current study finds that low and high levels of Bmp ligand are both necessary and sufficient to activate Intermediate and lateral Mesodermal gene expression, respectively, both in vivo and in vitro. Dose-dependent activation of Intermediate and lateral Mesodermal genes by Bmp signaling is cell-autonomous, as demonstrated by electroporation of the avian embryo with constitutively active Bmp receptors driven by promoters of varying strengths. In explant cultures, Bmp activation of Odd-skipped related 1 (Odd-1), the earliest known gene expressed in the Intermediate Mesoderm, is blocked by cyclohexamide, indicating that the activation of Odd-1 by Bmp signaling is translation-dependent. The data from this study are integrated with that of other studies to generate a model for the role of Bmp signaling in trunk Mesodermal patterning in which low levels of Bmp activate Intermediate Mesoderm gene expression by inhibition of repressors present in medial Mesoderm, whereas high levels of Bmp repress both medial and Intermediate Mesoderm gene expression and activate lateral plate genes.
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Cell fate specification along the anterior-posterior axis of the Intermediate Mesoderm.
Developmental dynamics : an official publication of the American Association of Anatomists, 2005Co-Authors: Hila Barak, Thomas M. Schultheiss, Lea Rosenfelder, Ram ReshefAbstract:The vertebrate Intermediate Mesoderm (IM) is highly patterned along the anterior-posterior (A-P) axis. In the chick embryo, the kidney tissue, which is a derivative of the IM, is generated only from IM located posterior to the sixth somite axial level, which also marks the border between cranial and trunk segments. The cellular and molecular mechanisms that govern the formation of the anterior border of the kidney morphogenetic field are currently unknown. In this study, we asked whether specific A-P patterning information is conveyed by the movement of cells through the primitive streak (PS) at different time points that consequently affects the expression of kidney genes, or by the environment that these cells encounter during their migration to the IM. In this study, we show that kidney-inductive signals are present along the whole axis, including anterior non-kidney-generating regions. These inductive signals are generated by tissues that are located medial to the anterior IM. We also demonstrate that cells that migrate through the PS of early embryonic stages (Hamburger and Hamilton stage 3-4 and earlier), which will give rise to anterior nonkidney IM, are competent to respond to these inductive factors. This prospective anterior IM tissue loses its competence to respond to kidney inducing signals during its migration from the PS to its final location in the anterior IM. We present here a model in which changes in cell competence determine the formation of the anterior border of kidney gene expression and discuss the possible evolutionary implications of this developmental mechanism.
Gregory R. Dressler - One of the best experts on this subject based on the ideXlab platform.
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chapter 2 early specification and patterning of the Intermediate Mesoderm genetics and epigenetics
Kidney Development Disease Repair and Regeneration, 2016Co-Authors: Egon Ranghini, Gregory R. DresslerAbstract:In the developing kidney, the Intermediate Mesoderm must be specified along the anteroposterior and mediolateral axes of the embryo, such that the kidney progenitor field is separated from the paraxial and lateral plate Mesoderm shortly after gastrulation. This region of Mesoderm generates both the metanephric mesenchyme and the ureteric bud epithelium, the two populations of progenitor cells that differentiate into nephrons and collecting ducts, respectively. Cell signaling pathways, nuclear DNA biding proteins, and epigenetic modifiers act in concert to imprint a kidney specific fate upon the Intermediate Mesoderm and its derivatives. This chapter describes the process of early kidney development and introduces the latest advancements in the understanding of how epigenetic modifications affect renal lineage specification and the maintenance of the renal cell phenotype in the adult.
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Evidence for Intermediate Mesoderm and kidney progenitor cell specification by Pax2 and PTIP dependent mechanisms.
Developmental biology, 2015Co-Authors: Egon Ranghini, Gregory R. DresslerAbstract:Activation of the Pax2 gene marks the Intermediate Mesoderm shortly after gastrulation, as the Mesoderm becomes compartmentalized into paraxial, Intermediate, and lateral plate. Using an EGFP knock-in allele of Pax2 to identify and sort cells of the Intermediate Mesodermal lineage, we compared gene expression patterns in EGFP positive cells that were heterozygous or homozygous null for Pax2. Thus, we identified critical regulators of Intermediate Mesoderm and kidney development whose expression depended on Pax2 function. In cell culture models, Pax2 is thought to recruit epigenetic modifying complex to imprint activating histone methylation marks through interactions with the adaptor protein PTIP. In kidney organ culture, conditional PTIP deletion showed that many Pax2 target genes, which were activated early in renal progenitor cells, remained on once activated, whereas Pax2 target genes expressed later in kidney development were unable to be fully activated without PTIP. In Pax2 mutants, we also identified a set of genes whose expression was up-regulated in EGFP positive cells and whose expression was consistent with a cell fate transformation to paraxial Mesoderm and its derivatives. These data provide evidence that Pax2 specifies the Intermediate Mesoderm and renal epithelial cells through epigenetic mechanisms and in part by repressing paraxial Mesodermal fate.
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Two novel EGFP insertion alleles reveal unique aspects of Pax2 function in embryonic and adult kidneys
Developmental biology, 2012Co-Authors: Abdul Soofi, Inna Levitan, Gregory R. DresslerAbstract:The Pax2 gene encodes a DNA binding protein with multiple functions in the developing Intermediate Mesoderm and urogenital tract. Loss of Pax2 in mice results in the complete absence of kidneys, ureters, and sex specific epithelial structures derived from the Intermediate Mesoderm in both males and females. In this report, we describe two new alleles of Pax2 created by inserting the enhanced green fluorescent protein coding region into the 5' untranslated leader sequence. One allele is a hypomorph that generates less protein and exhibits structural defects in kidneys and ureters upon homozygosity. A second allele is a true null that can be used to image Pax2 expressing cells in a mutant background. Organ culture and embryo analyses point to a loss of epithelial cell polarity and increased mobility in cells that have deleted Pax2 function. These experiments provide new insight into the role of Pax2 protein levels in determining correct renal architecture and cell fate. These new Pax2 alleles are valuable genetic reagents for in vivo studies of urogenital development.
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Patterning and early cell lineage decisions in the developing kidney: the role of Pax genes
Pediatric nephrology (Berlin Germany), 2011Co-Authors: Gregory R. DresslerAbstract:Specification of the Intermediate Mesoderm and the epithelial derivatives that will make the mammalian kidney depends on the concerted action of many transcription factors and signaling proteins. Among the earliest genes expressed in the nephric duct and surrounding mesenchyme is Pax2, whose function is essential for making and maintaining the epithelium. The Pax2 protein is subject to phosphorylation in response to signals that activate the c-Jun N-terminal kinase pathway, including Wnts and BMPs. In cell culture systems, Pax2 is know to recruit components of a histone H3 lysine 4 methyltransferase complex to specific DNA sites to alter the pattern of histone modifications and determine gene expression. This epigenetic function may underlie the ability of Pax2 and similar proteins to maintain cell lineages during development.
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Epigenetics, Development, and the Kidney
Journal of the American Society of Nephrology : JASN, 2008Co-Authors: Gregory R. DresslerAbstract:How cells partition the genome into active and inactive genes and how that information is established and propagated during embryonic development are fundamental to maintaining the normal differentiated state. The molecular mechanisms of epigenetic action and cellular memory are increasingly amenable to study primarily as a result of the rapid progress in the area of chromatin biology. Methylation of DNA and modification of histones are critical epigenetic marks that establish active and silent chromatin domains. During development of the kidney, DNA-binding factors such as Pax2/8, which are essential for the Intermediate Mesoderm and the renal epithelial lineage, could provide the locus and tissue specificity for histone methylation and chromatin remodeling and thus establish a kidney-specific fate. The role of epigenetic modifications in development and disease is under intense investigation and has already affected our view of cancer and aging.
Richard G. James - One of the best experts on this subject based on the ideXlab platform.
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a role for vg1 nodal signaling in specification of the Intermediate Mesoderm
Development, 2013Co-Authors: Britannia M. Fleming, Richard G. James, Ronit Yelin, Thomas M. SchultheissAbstract:The Intermediate Mesoderm (IM) is the embryonic source of all kidney tissue in vertebrates. The factors that regulate the formation of the IM are not yet well understood. Through investigations in the chick embryo, the current study identifies and characterizes Vg1/Nodal signaling (henceforth referred to as ‘Nodal-like signaling’) as a novel regulator of IM formation. Excess Nodal-like signaling at gastrulation stages resulted in expansion of the IM at the expense of the adjacent paraxial Mesoderm, whereas inhibition of Nodal-like signaling caused repression of IM gene expression. IM formation was sensitive to levels of the Nodal-like pathway co-receptor Cripto and was inhibited by a truncated form of the secreted molecule cerberus, which specifically blocks Nodal, indicating that the observed effects are specific to the Nodal-like branch of the TGFβ signaling pathway. The IM-promoting effects of Nodal-like signaling were distinct from the known effects of this pathway on Mesoderm formation and left-right patterning, a finding that can be attributed to specific time windows for the activities of these Nodal-like functions. Finally, a link was observed between Nodal-like and BMP signaling in the induction of IM. Activation of IM genes by Nodal-like signaling required an active BMP signaling pathway, and Nodal-like signals induced phosphorylation of Smad1/5/8, which is normally associated with activation of BMP signaling pathways. We postulate that Nodal-like signaling regulates IM formation by modulating the IM-inducing effects of BMP signaling.
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A role for Vg1/Nodal signaling in specification of the Intermediate Mesoderm.
Development (Cambridge England), 2013Co-Authors: Britannia M. Fleming, Richard G. James, Ronit Yelin, Thomas M. SchultheissAbstract:The Intermediate Mesoderm (IM) is the embryonic source of all kidney tissue in vertebrates. The factors that regulate the formation of the IM are not yet well understood. Through investigations in the chick embryo, the current study identifies and characterizes Vg1/Nodal signaling (henceforth referred to as ‘Nodal-like signaling’) as a novel regulator of IM formation. Excess Nodal-like signaling at gastrulation stages resulted in expansion of the IM at the expense of the adjacent paraxial Mesoderm, whereas inhibition of Nodal-like signaling caused repression of IM gene expression. IM formation was sensitive to levels of the Nodal-like pathway co-receptor Cripto and was inhibited by a truncated form of the secreted molecule cerberus, which specifically blocks Nodal, indicating that the observed effects are specific to the Nodal-like branch of the TGFβ signaling pathway. The IM-promoting effects of Nodal-like signaling were distinct from the known effects of this pathway on Mesoderm formation and left-right patterning, a finding that can be attributed to specific time windows for the activities of these Nodal-like functions. Finally, a link was observed between Nodal-like and BMP signaling in the induction of IM. Activation of IM genes by Nodal-like signaling required an active BMP signaling pathway, and Nodal-like signals induced phosphorylation of Smad1/5/8, which is normally associated with activation of BMP signaling pathways. We postulate that Nodal-like signaling regulates IM formation by modulating the IM-inducing effects of BMP signaling.
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Bmp signaling promotes Intermediate Mesoderm gene expression in a dose-dependent, cell-autonomous and translation-dependent manner
Developmental biology, 2005Co-Authors: Richard G. James, Thomas M. SchultheissAbstract:The Intermediate Mesoderm lies between the somites and the lateral plate and is the source of all kidney tissue in the developing vertebrate embryo. While bone morphogenetic protein (Bmp) signaling is known to regulate Mesodermal cell type determination along the medio-lateral axis, its role in Intermediate Mesoderm formation has not been well characterized. The current study finds that low and high levels of Bmp ligand are both necessary and sufficient to activate Intermediate and lateral Mesodermal gene expression, respectively, both in vivo and in vitro. Dose-dependent activation of Intermediate and lateral Mesodermal genes by Bmp signaling is cell-autonomous, as demonstrated by electroporation of the avian embryo with constitutively active Bmp receptors driven by promoters of varying strengths. In explant cultures, Bmp activation of Odd-skipped related 1 (Odd-1), the earliest known gene expressed in the Intermediate Mesoderm, is blocked by cyclohexamide, indicating that the activation of Odd-1 by Bmp signaling is translation-dependent. The data from this study are integrated with that of other studies to generate a model for the role of Bmp signaling in trunk Mesodermal patterning in which low levels of Bmp activate Intermediate Mesoderm gene expression by inhibition of repressors present in medial Mesoderm, whereas high levels of Bmp repress both medial and Intermediate Mesoderm gene expression and activate lateral plate genes.
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The forkhead genes, Foxc1 and Foxc2 , regulate paraxial versus Intermediate Mesoderm cell fate
Developmental biology, 2004Co-Authors: Bettina Wilm, Richard G. James, Thomas M. Schultheiss, Brigid L.m. HoganAbstract:During vertebrate embryogenesis, the newly formed Mesoderm is allocated to the paraxial, Intermediate, and lateral domains, each giving rise to different cell and tissue types. Here, we provide evidence that the forkhead genes, Foxc1 and Foxc2, play a role in the specification of Mesoderm to paraxial versus Intermediate fates. Mouse embryos lacking both Foxc1 and Foxc2 show expansion of Intermediate Mesoderm markers into the paraxial domain, lateralization of somite patterning, and ectopic and disorganized mesonephric tubules. In gain of function studies in the chick embryo, Foxc1 and Foxc2 negatively regulate Intermediate Mesoderm formation. By contrast, their misexpression in the prospective Intermediate Mesoderm appears to drive cells to acquire paraxial fate, as revealed by expression of the somite markers Pax7 and Paraxis. Taken together, the data indicate that Foxc1 and Foxc2 regulate the establishment of paraxial versus Intermediate Mesoderm cell fates in the vertebrate embryo.
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Patterning of the avian Intermediate Mesoderm by lateral plate and axial tissues.
Developmental biology, 2003Co-Authors: Richard G. James, Thomas M. SchultheissAbstract:Amniote kidney tissue is derived from the Intermediate Mesoderm (IM), a strip of Mesoderm that lies between the somites and the lateral plate. While much has been learned concerning the later events which regulate the differentiation of IM into tubules and other types of kidney tissue, much less is known concerning the earlier events which regulate formation of the IM itself. In the current study, the chick pronephros was used as a model system to identify tissues that play a role in patterning the IM and the critical time periods during which such patterning events take place. Explant studies revealed that the prospective pronephric IM is already specified to express kidney genes by stage 6, shortly after its gastrulation through the primitive streak, and earlier than previously reported. Transplant and explant experiments revealed that the lateral plate contains an activity that can repress IM formation in tissues that are already specified to express IM genes. In contrast, Hensen's node can promote formation of IM in the lateral plate. Paraxial tissues (presomitic Mesoderm plus neural plate and notochord) were found to influence the morphogenesis of the nephric duct, but did not induce IM tissue to an appreciable extent. Combining lateral plate and paraxial tissue in vivo or in vitro led to induction of IM genes in the paraxial Mesoderm but not in the lateral plate Mesoderm. Based on these results and those of others, we propose a two-step model for the patterning of the IM. While tissue is still in the primitive streak, the prospective IM is relatively uncommitted. By stage 6, shortly after cells leave the primitive streak, a field of cells is generate which is specified to give rise to IM (Step 1). Subsequently, competing signals from the lateral plate and axial tissues modulate the number of cells that commit to an IM fate (Step 2).
Britannia M. Fleming - One of the best experts on this subject based on the ideXlab platform.
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a role for vg1 nodal signaling in specification of the Intermediate Mesoderm
Development, 2013Co-Authors: Britannia M. Fleming, Richard G. James, Ronit Yelin, Thomas M. SchultheissAbstract:The Intermediate Mesoderm (IM) is the embryonic source of all kidney tissue in vertebrates. The factors that regulate the formation of the IM are not yet well understood. Through investigations in the chick embryo, the current study identifies and characterizes Vg1/Nodal signaling (henceforth referred to as ‘Nodal-like signaling’) as a novel regulator of IM formation. Excess Nodal-like signaling at gastrulation stages resulted in expansion of the IM at the expense of the adjacent paraxial Mesoderm, whereas inhibition of Nodal-like signaling caused repression of IM gene expression. IM formation was sensitive to levels of the Nodal-like pathway co-receptor Cripto and was inhibited by a truncated form of the secreted molecule cerberus, which specifically blocks Nodal, indicating that the observed effects are specific to the Nodal-like branch of the TGFβ signaling pathway. The IM-promoting effects of Nodal-like signaling were distinct from the known effects of this pathway on Mesoderm formation and left-right patterning, a finding that can be attributed to specific time windows for the activities of these Nodal-like functions. Finally, a link was observed between Nodal-like and BMP signaling in the induction of IM. Activation of IM genes by Nodal-like signaling required an active BMP signaling pathway, and Nodal-like signals induced phosphorylation of Smad1/5/8, which is normally associated with activation of BMP signaling pathways. We postulate that Nodal-like signaling regulates IM formation by modulating the IM-inducing effects of BMP signaling.
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A role for Vg1/Nodal signaling in specification of the Intermediate Mesoderm.
Development (Cambridge England), 2013Co-Authors: Britannia M. Fleming, Richard G. James, Ronit Yelin, Thomas M. SchultheissAbstract:The Intermediate Mesoderm (IM) is the embryonic source of all kidney tissue in vertebrates. The factors that regulate the formation of the IM are not yet well understood. Through investigations in the chick embryo, the current study identifies and characterizes Vg1/Nodal signaling (henceforth referred to as ‘Nodal-like signaling’) as a novel regulator of IM formation. Excess Nodal-like signaling at gastrulation stages resulted in expansion of the IM at the expense of the adjacent paraxial Mesoderm, whereas inhibition of Nodal-like signaling caused repression of IM gene expression. IM formation was sensitive to levels of the Nodal-like pathway co-receptor Cripto and was inhibited by a truncated form of the secreted molecule cerberus, which specifically blocks Nodal, indicating that the observed effects are specific to the Nodal-like branch of the TGFβ signaling pathway. The IM-promoting effects of Nodal-like signaling were distinct from the known effects of this pathway on Mesoderm formation and left-right patterning, a finding that can be attributed to specific time windows for the activities of these Nodal-like functions. Finally, a link was observed between Nodal-like and BMP signaling in the induction of IM. Activation of IM genes by Nodal-like signaling required an active BMP signaling pathway, and Nodal-like signals induced phosphorylation of Smad1/5/8, which is normally associated with activation of BMP signaling pathways. We postulate that Nodal-like signaling regulates IM formation by modulating the IM-inducing effects of BMP signaling.
Alan O Perantoni - One of the best experts on this subject based on the ideXlab platform.
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non canonical wnt5a ror2 signaling regulates kidney morphogenesis by controlling Intermediate Mesoderm extension
Human Molecular Genetics, 2014Co-Authors: Kangsun Yun, Rieko Ajima, Nirmala Sharma, Frank Costantini, Susan Mackem, Mark Lewandoski, Terry P Yamaguchi, Alan O PerantoniAbstract:Congenital anomalies of the kidney and urinary tract (CAKUT) affect about 1 in 500 births and are a major cause of morbidity in infants. Duplex collecting systems rank among the most common abnormalities of CAKUT, but the molecular basis for this defect is poorly understood. In mice, conditional deletion of Wnt5a in Mesoderm results in bilateral duplex kidney and ureter formation. The ureteric buds (UBs) in mutants emerge as doublets from the Intermediate Mesoderm (IM)-derived nephric duct (ND) without anterior expansion of the glial cell line-derived neurotrophic factor (Gdnf) expression domain in the surrounding mesenchyme. Wnt5a is normally expressed in a graded manner at the posterior end of the IM, but its expression is down-regulated prior to UB outgrowth at E10.5. Furthermore, ablation of Wnt5a in the Mesoderm with an inducible Cre at E7.5 results in duplex UBs, whereas ablation at E8.5 yields normal UB outgrowth, demonstrating that Wnt5a functions in IM development well before the formation of the metanephros. In mutants, the posterior ND is duplicated and surrounding Pax2-positive mesenchymal cells persist in the nephric cord, suggesting that disruption of normal ND patterning prompts the formation of duplex ureters and kidneys. Ror2 homozygous mutants, which infrequently yield duplex collecting systems, show a dramatic increase in incidence with the additional deletion of one copy of Wnt5a, implicating this receptor in non-canonical Wnt5a signaling during IM development. This work provides the first evidence of a role of Wnt5a/Ror2 signaling in IM extension and offers new insights into the etiology of CAKUT and possible involvement of Wnt5a/Ror2 mutations.
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Non-canonical Wnt5a/Ror2 signaling regulates kidney morphogenesis by controlling Intermediate Mesoderm extension
Human molecular genetics, 2014Co-Authors: Kangsun Yun, Rieko Ajima, Nirmala Sharma, Frank Costantini, Susan Mackem, Mark Lewandoski, Terry P Yamaguchi, Alan O PerantoniAbstract:Congenital anomalies of the kidney and urinary tract (CAKUT) affect about 1 in 500 births and are a major cause of morbidity in infants. Duplex collecting systems rank among the most common abnormalities of CAKUT, but the molecular basis for this defect is poorly understood. In mice, conditional deletion of Wnt5a in Mesoderm results in bilateral duplex kidney and ureter formation. The ureteric buds (UBs) in mutants emerge as doublets from the Intermediate Mesoderm (IM)-derived nephric duct (ND) without anterior expansion of the glial cell line-derived neurotrophic factor (Gdnf) expression domain in the surrounding mesenchyme. Wnt5a is normally expressed in a graded manner at the posterior end of the IM, but its expression is down-regulated prior to UB outgrowth at E10.5. Furthermore, ablation of Wnt5a in the Mesoderm with an inducible Cre at E7.5 results in duplex UBs, whereas ablation at E8.5 yields normal UB outgrowth, demonstrating that Wnt5a functions in IM development well before the formation of the metanephros. In mutants, the posterior ND is duplicated and surrounding Pax2-positive mesenchymal cells persist in the nephric cord, suggesting that disruption of normal ND patterning prompts the formation of duplex ureters and kidneys. Ror2 homozygous mutants, which infrequently yield duplex collecting systems, show a dramatic increase in incidence with the additional deletion of one copy of Wnt5a, implicating this receptor in non-canonical Wnt5a signaling during IM development. This work provides the first evidence of a role of Wnt5a/Ror2 signaling in IM extension and offers new insights into the etiology of CAKUT and possible involvement of Wnt5a/Ror2 mutations.