Satu Kuure

University of Helsinki | HY · Medicum

The GLE1 protein is an enigmatic factor of RNA processing, associated with multiple developmental disorders including lethal congenital contracture syndrome 1 (LCCS1). Using in vivo genetic engineering to study disturbed GLE1 functions under physiological conditions we demonstrate that inactivation of Gle1 impedes cellular function and organization...

Despite the increasing interest in cellulose-derived materials in biomedical research, there remains a significant gap in comprehensive in vivo analyses of cellulosic materials obtained from various sources and processing methods. To explore durable alternatives to synthetic medical meshes, we evaluated the in vivo biocompatibility of bacterial nan...

Liver is the key hub of systemic energy metabolism and growth regulation, yet its roles in mitochondrial disease pathophysiology remain relatively understudied. Bcs1l p.S78G knock-in mice, carrying a patient mutation causing respiratory complex III (CIII)-deficiency, present juvenile-onset liver and kidney disease, growth restriction, lipodystrophy...

Branching morphogenesis is a characteristic feature of many essential organs, such as the lung and kidney, and most glands, and is the net result of two tissue behaviors: branch point initiation and elongation. Each branched organ has a distinct architecture customized to its physiological function, but how patterning occurs in these ramified tubul...

Background Branching morphogenesis orchestrates organogenesis in many tissues including kidney, where ureteric bud branching determines kidney size and nephron number. Defects in branching morphogenesis result in congenital renal anomalies which manifest as deviations in size, function, and nephron number thus critically compromising the lifelong r...

The immunoglobulin (Ig) superfamily members are involved in cell adhesion and migration, complex multistep processes that play critical roles in embryogenesis, wound healing, tissue formation, and many other processes, but their specific functions during embryonic development remain unclear. Here, we have studied the function of the immunoglobulin...

Isolated populations have been valuable for the discovery of rare monogenic diseases and their causative genetic variants. Finnish disease heritage (FDH) is an example of a group of hereditary monogenic disorders caused by single major, usually autosomal-recessive, variants enriched in the population due to several past genetic drift events. Intere...

Kidneys develop via iterative branching of the ureteric epithelial tree and subsequent nephrogenesis at the branch points. Nephrons form in the cap mesenchyme as the metanephric mesenchyme (MM) condenses around the epithelial ureteric buds (UBs). Previous work demonstrated that FGF8 is important for the survival of nephron progenitor cells (NPCs),...

Nephron endowment is defined by fetal kidney growth and crucially dictates renal health in adults. Defects in the molecular regulation of nephron progenitors contribute to only a fraction of reduced nephron mass cases, suggesting alternative causative mechanisms. The importance of MAPK/ERK activation in nephron progenitor maintenance has been previ...

Branching morphogenesis is a characteristic feature of many essential organs such as the lung, kidney, and most glands, and the net result of two tissue behaviors: branch point initiation and elongation. Each branched organ has a distinct architecture customized to its physiological function, but how patterning occurs in these ramified tubular stru...

Background MAPK/ERK signaling is a well-known mediator of extracellular stimuli controlling intracellular responses to growth factors and mechanical cues. The critical requirement of MAPK/ERK signaling for embryonic stem cell maintenance is demonstrated, but specific functions in progenitor regulation during embryonic development, and in particular...

Kidneys develop via iterative branching of the ureteric epithelial tree and subsequent nephrogenesis at the branch points. Nephrons form in the cap mesenchyme as the metanephric mesenchyme (MM) condenses around the epithelial ureteric buds (UBs). Previous work demonstrated that FGF8 is important for the survival of nephron progenitor cells (NPCs),...

The modification of genes in animal models has evidently and comprehensively improved our knowledge on proteins and signaling pathways in human physiology and pathology. In this review, we discuss almost 40 monogenic rare diseases that are enriched in the Finnish population and defined as the Finnish disease heritage (FDH). We will highlight how ge...

Nephron endowment is defined by fetal kidney growth and it critically dictates renal health in adults. Despite the advances in understanding the molecular regulation of nephron progenitor maintenance, propagation, and differentiation, the causes for low congenital nephron count and contribution of basic metabolism to nephron progenitor regulation r...

Transforming growth factor-beta (TGFβ) is a multifunctional cytokine with a well-established role in mammary gland development and both oncogenic and tumor-suppressive functions. The extracellular matrix (ECM) indirectly regulates TGFβ activity by acting as a storage compartment of latent-TGFβ, but how TGFβ is released from the ECM via proteolytic...

Nephron endowment, defined during the fetal period, dictates renal and related cardiovascular health throughout life. We show here that, despite its negative effects on kidney growth, genetic increase of GDNF prolongs the nephrogenic program beyond its normal cessation. Multi-stage mechanistic analysis revealed that excess GDNF maintains nephron pr...

The adult mammalian kidney is a poorly regenerating organ that lacks the stem cells that could replenish functional homeostasis similarly to, e.g., skin or the hematopoietic system. Unlike a mature kidney, the embryonic kidney hosts at least three types of lineage-specific stem cells that give rise to (a) a ureter and collecting duct system, (b) ne...

The 16th transgenic technology (TT) meeting of the International Society of Transgenic technology (ISTT) took place on October 26–29th 2020 and was quite unique as it was the first-ever virtual meeting in the history of ISTT events. Dr. Rebecca Haffner-Krausz at Weizmann Institute of Science, Israel, was the local organizer of the meeting, which at...

Due to poor regenerative capacity of adult kidneys, nephron endowment defined by the nephrogenic program during the fetal period dictates renal and related cardiovascular health throughout life. We show that the neurotropic factor GDNF, which is in clinical trials for Parkinson's disease, is capable of prolonging the nephrogenic program beyond its...

Congenital anomalies of the kidney and urinary tract (CAKUT) are common birth defects, which cause the majority of chronic kidney diseases in children. CAKUT covers a wide range of malformations that derive from deficiencies in embryonic kidney and lower urinary tract development, including renal aplasia, hypodysplasia, hypoplasia, ectopia, and dif...

The demand for single-cell level data is constantly increasing within life sciences. In order to meet this demand, robust cell segmentation methods that can tackle challenging in vivo tissues with complex morphology are required. However, currently available cell segmentation and volumetric analysis methods perform poorly on 3D images. Here, we gen...

Kidney mesenchyme (KM) and nephron progenitors (NPs) depend on WNT activity, and their culture in vitro requires extensive repertoire of recombinant proteins and chemicals. Here we established a robust, simple culture of mouse KM using a combination of 3D Matrigel and growth media supplemented with Fibroblast Growth Factor 2 (FGF2) and Src inhibito...

Congenital anomalies of the kidney and urinary tract (CAKUT) are common birth defects derived from abnormalities in renal differentiation during embryogenesis. CAKUT is the major cause of end-stage renal disease and chronic kidney diseases in children, but its genetic causes remain largely unresolved. Here we discuss advances in the understanding o...

Mechanisms controlling ureter lenght and the position of the kidney are poorly understood. Glial cell-line derived neurotrophic factor (GDNF) induced RET signaling is critical for ureteric bud outgrowth, but the function of endogenous GDNF in further renal differentiation and urogenital system development remains discursive. Here we analyzed mice w...

Congenital anomalies of the kidney and urinary tract (CAKUT) are common birth defects deriving from abnormalities in renal differentiation during embryogenesis. CAKUT is the major cause of end-stage renal disease and chronic kidney diseases in children, but its genetic causes remain largely unresolved. Here we discuss advances in the understanding...

FAT4 mutations lead to several human diseases that disrupt the normal development of the kidney. However, the underlying mechanism remains elusive. In studying the duplex kidney phenotypes observed upon deletion of Fat4 in mice, we have uncovered an interaction between the atypical cadherin FAT4 and RET, a tyrosine kinase receptor essential for kid...

Kidney organogenesis has been a widely used classical model system to study inductive tissue interactions that guide differentiation of many organs. The basis for this is in the pioneering work done during the early 1950s when the conditions of how to support ex vivo growth and differentiation of developing kidneys were revealed. Importantly, cultu...

Classically, trophic factors are considered as proteins which support neurons in their growth, survival, and differentiation. However, most neurotrophic factors also have important functions outside of the nervous system. Especially essential renal growth and differentiation regulators are glial cell line-derived neurotrophic factor (GDNF), bone mo...

Video S2. Live-Imaging of FRET Biosensor for ERK Activation in FGF2-Treated E12.5 Kidney (315 min)

Video S1. Live-Imaging of FRET Biosensor for ERK Activation in E12.5 Kidney (480 min)

Video S4. Live-Imaging of Sphere Formation in Dissociated Nephron Progenitors Treated with FGF2 (24 hr)

Video S3. Live-Imaging of FRET Biosensor for ERK Activation in MEK-Inhibited E12.5 Kidney (590 min)

The in vivo niche and basic cellular properties of nephron progenitors are poorly described. Here we studied the cellular organization and function of the MAPK/ERK pathway in nephron progenitors. Live-imaging of ERK activity by a Fo¨rster resonance energy transfer biosensor revealed a dynamic activation pattern in progenitors, whereas differentiati...

STATEMENT Both plasticity and genetic variation in kidney morphology and candidate gene expression have likely facilitated adaptation to permanent low salinity residency in threespine stickleback populations from the Baltic Sea. ABSTRACT Novel physiological challenges in different environments can promote the evolution of divergent phenotypes, eith...

In Parkinson's disease midbrain dopaminergic neurons degenerate and die. Oral medications and deep brain stimulation can relieve the initial symptoms, but the disease continues to progress. Growth factors that might support the survival, enhance the activity, or even regenerate degenerating dopamine neurons have been tried with mixed results in pat...

[This corrects the article DOI: 10.1371/journal.pgen.1005710.].

Degeneration of nigrostriatal dopaminergic system is the principal lesion in Parkinson's disease. Because glial cell line-derived neurotrophic factor (GDNF) promotes survival of dopamine neurons in vitro and in vivo, intracranial delivery of GDNF has been attempted for Parkinson's disease treatment but with variable success. For improving GDNF-base...

The pluripotency and self-renewal capacity of embryonic stem (ES) cells is regulated by several transcription factors. Here, we show that the ETS-related transcription factors ETV4 and ETV5 (ETV4/5) are specifically expressed in undifferentiated ES cells, and suppression of Oct3/4 results in down-regulation of ETV4/5. Simultaneous deletion of ETV4...

Although the growth factor (GF) signaling guiding renal branching is well characterized, the intracellular cascades mediating GF functions are poorly understood. We studied mitogen-activated protein kinase (MAPK) pathway specifically in the branching epithelia of developing kidney by genetically abrogating the pathway activity in mice lacking simul...

Kidney development has been widely used as a model system to study molecular control of inductive tissue interactions and mechanisms through which branching organs form. Due to lacking or poor methods, less focus has been in understanding details of cellular events that accomplish example ureteric bud (UB) branching. In order to form a branch point...

This is a meeting abstract, not a research article

Glial cell line-derived neurotrophic factor (GDNF) is indispensable for ureteric budding and branching. If applied exogenously, GDNF promotes ectopic ureteric buds from the Wolffian duct. Although several downstream effectors of GDNF are known, the identification of early response genes is incomplete. Here, microarray screening detected several GDN...

Branching morphogenesis is a central developmental mechanism utilized in the morphogenesis of several organs including lung, liver, salivary gland and kidney. The molecular control of the basic process of renal differentiation, the ureteric bud (UB) branching, has been in the focus of extensive studies while the cellular events, such as migration a...

The tip of the ureteric bud in the metanephric kidney is a signaling center inducing formation of mesenchyme-derived nephrons, and simultaneously it responds by growth and branching to signals from the mesenchyme. Here we report that Visinin like 1 (Vsnl1) is a new ureteric bud tip marker, which encodes for a neuronal calcium sensor—Vsnl1 protein w...

Signaling by GDNF through the Ret receptor tyrosine kinase is required for the normal formation, growth and branching of the ureteric bud (UB) during kidney development. However, the precise role of GDNF/Ret signaling in this process, and the specific responses of UB cells to GDNF, remain to be fully elucidated. Recent studies provide new insight i...

Double ureters in Dstn-/- and delayed UB branching in Cfl1+/-;Dstn-/- embryos. (A-B), double ureter (arrows) in a Dstn-/- embryo (B) compared to single ureter in control (A), at E11.5. (C-F), Hoxb7/myrVenus transgene expressed in ureteric bud epithelium reveals slightly delayed branching morphogenesis in a Cfl1+/-;Dstn-/- kidney at E12.5. C and E,...

Establishment of primary UB cell cultures. Ureteric buds were isolated free of metanephric mesenchyme and plated in fibronectin coated wells, where they attach and form monolayers. (A), Primary ureteric epithelial cells of all genotypes (Dstn+/- is shown) were relatively quiescent in culture, as shown by the paucity of Ki67+ (green) proliferative c...

F-actin distribution is normal in double mutant Wolffian duct at E10.5. Embryos were stained for phalloidin (red) to visualize F-actin and for calbindin (green) to demarcate the Wolffian duct and ureteric bud epithelium. (A), Wild type embryo. (A') shows higher magnification of F-actin distribution in wild type Wolffian duct. F-actin remains normal...

Normal expression of Ret and Wnt11 in Cfl1;Dstn double mutant UBs. (A-D) Control and double mutant kidneys at E11.5 (A, B) or E11.5+18hrs of culture (C, D) were used for Ret whole mount in situ hybridization. (A) control (no Cre; Cfl1F/+; Dstn-/-), (B) double mutant. The UBs are demarcated by dotted lines. (C) control (Hoxb7/CreGFP; Cfl1+/+; Dstn+/...

The actin depolymerizing factors (ADFs) play important roles in several cellular processes that require cytoskeletal rearrangements, such as cell migration, but little is known about the in vivo functions of ADFs in developmental events like branching morphogenesis. While the molecular control of ureteric bud (UB) branching during kidney developmen...

Signaling by the Ret receptor tyrosine kinase promotes cell movements in the Wolffian duct that give rise to the first ureteric bud tip, initiating kidney development. Although the ETS transcription factors Etv4 and Etv5 are known to be required for mouse kidney development and to act downstream of Ret, their specific functions are unclear. Here, w...

Glial cell line-derived neurotrophic factor signaling through the Ret receptor tyrosine kinase is crucial for ureteric bud branching morphogenesis during kidney development, yet few of the downstream genes are known. Here we show that the ETS transcription factors Etv4 and Etv5 are positively regulated by Ret signaling in the ureteric bud tips. Mic...

WNT/beta-catenin signaling has an established role in nephron formation during kidney development. Yet, the role of beta-catenin during ureteric morphogenesis in vivo is undefined. We generated a murine genetic model of beta-catenin deficiency targeted to the ureteric bud cell lineage. Newborn mutant mice demonstrated bilateral renal aplasia or ren...

The most severe forms of motoneuron disease manifest in utero are characterized by marked atrophy of spinal cord motoneurons and fetal immobility. Here, we report that the defective gene underlying lethal motoneuron syndrome LCCS1 is the mRNA export mediator GLE1. Our finding of mutated GLE1 exposes a common pathway connecting the genes implicated...

Wnt proteins are required for induction of nephrons in mouse metanephric kidneys, but the downstream pathways that mediate tubule induction and epithelial differentiation have remained obscure. The intracellular mechanisms by which Wnt signaling mediates nephron induction in embryonic kidney mesenchymes were studied. First is shown that transient e...

Glial-Cell-Line-Derived Neurotrophic Factor (GDNF) is the major mesenchyme-derived regulator of ureteric budding and branching during nephrogenesis. The ligand activates on the ureteric bud epithelium a receptor complex composed of Ret and GFRalpha1. The upstream regulators of the GDNF receptors are poorly known. A Notch ligand, Jagged1 (Jag1), co-...

Development of an organ is directed by cell and tissue interactions and these also occur during the formation of functional kidney. During vertebrate development inductive signalling between mesenchyme and epithelium controls the organogenesis of all three kinds of kidneys: pronephros, mesonephros and metanephros. In higher animals the metanephros...

Members of the human cytochrome P450 2A (CYP2A) subfamily are known to metabolize several promutagens, procarcinogens, and pharmaceuticals. In this study, the expression of the three genes found in the human CYP2A gene cluster was investigated in the liver and several extrahepatic tissues by gene-specific reverse transcriptase-polymerase chain reac...

The permanent mammalian kidney (metanephros) develops as a result of complex reciprocal tissue interactions between a ureteric epithelium and the renal mesenchyme. The overall goal of the research in this thesis was to gain data that will eventually help in elucidating the formation of congenital renal malformations. The experiments in my thesis ai...