β-catenin regulates the formation of multiple nephron segments in the mouse kidney

Abstract The nephron is composed of distinct segments that perform unique physiological functions. Little is known about how multipotent nephron progenitor cells differentiate into different nephron segments. It is well known that β-catenin signaling regulates the maintenance and commitment of mesenchymal nephron progenitors during kidney development. However, it is not fully understood how it regulates nephron segmentation after nephron progenitors undergo mesenchymal-to-epithelial transition. To address this, we performed β-catenin loss-of-function and gain-of-function studies in epithelial nephron progenitors in the mouse kidney. Consistent with a previous report, the formation of the renal corpuscle was defective in the absence of β-catenin. Interestingly, we found that epithelial nephron progenitors lacking β-catenin were able to form presumptive proximal tubules but that they failed to further develop into differentiated proximal tubules, suggesting that β-catenin signaling plays a critical role in proximal tubule development. We also found that epithelial nephron progenitors lacking β-catenin failed to form the distal tubules. Expression of a stable form of β-catenin in epithelial nephron progenitors blocked the proper formation of all nephron segments, suggesting tight regulation of β-catenin signaling during nephron segmentation. This work shows that β-catenin regulates the formation of multiple nephron segments along the proximo-distal axis of the mammalian nephron.

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Wnt/β-catenin signaling is required for the development of multiple nephron segments

10.1101/488718 ◽

2018 ◽

Author(s):

Patrick Deacon ◽

Charles W Concodora ◽

Eunah Chung ◽

Joo-Seop Park

Keyword(s):

Kidney Development ◽

Critical Role ◽

Proximal Tubules ◽

Loss Of Function ◽

Constitutive Activation ◽

Nephron Segments ◽

Mesenchymal To Epithelial Transition ◽

Nephron Progenitors ◽

Distal Tubules ◽

Nephron Progenitor

The nephron is composed of distinct segments that perform unique physiological functions to generate urine. Little is known about how multipotent nephron progenitor cells differentiate into different nephron segments. It is well known that Wnt/β-catenin signaling regulates the maintenance and commitment of mesenchymal nephron progenitors during kidney development. However, it is not fully understood how it regulates nephron patterning after nephron progenitors undergo mesenchymal-to-epithelial transition. To address this, we performed β-catenin loss-of-function and gain-of-function studies in epithelial nephron progenitors in the mouse kidney. Consistent with a previous report, the formation of the renal corpuscle was defective in the absence of β-catenin. Interestingly, we found that epithelial nephron progenitors lacking β-catenin were able to form presumptive proximal tubules but that they failed to further develop into differentiated proximal tubules, suggesting that Wnt/β-catenin signaling plays a critical role in proximal tubule development. We also found that epithelial nephron progenitors lacking β-catenin failed to form the distal tubules. Constitutive activation of Wnt/β-catenin signaling blocked the proper formation of all nephron segments, suggesting tight regulation of Wnt/β-catenin signaling during nephron patterning. This work shows that Wnt/β-catenin signaling regulates the patterning of multiple nephron segments along the proximo-distal axis of the mammalian nephron.

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Nephron-specific expression of components of the renin–angiotensin–aldosterone system in the mouse kidney

Journal of the Renin-Angiotensin-Aldosterone System ◽

10.1177/1470320311432184 ◽

2012 ◽

Vol 13 (1) ◽

pp. 46-55 ◽

Cited By ~ 7

Author(s):

Stephan W Reinhold ◽

Bernd Krüger ◽

Caroline Barner ◽

Flavius Zoicas ◽

Martin C Kammerl ◽

...

Keyword(s):

Mouse Kidney ◽

Proximal Tubules ◽

Thick Ascending Limb ◽

Specific Expression ◽

Renin Angiotensin Aldosterone System ◽

Renin Angiotensin ◽

Nephron Segments ◽

Specific Distribution ◽

Convoluted Tubules ◽

Proximal Convoluted Tubules

Introduction: The renin–angiotensin–aldosterone system (RAAS) plays an integral role in the regulation of blood pressure, electrolyte and fluid homeostasis in mammals. The capability of the different nephron segments to form components of the RAAS is only partially known. This study therefore aimed to characterize the nephron-specific expression of RAAS components within the mouse kidney. Materials and methods: Defined nephron segments of adult C57B/16 mice were microdissected after collagenase digestion. The gene expression of renin, angiotensinogen (AGT), angiotensin-converting enzyme (ACE), angiotensin II receptors 1a (AT1a), 1b (AT1b), and 2 (AT2) was assessed by reverse transcriptase polymerase chain reaction (RT-PCR). Results: Renin mRNA was present in glomeruli, in proximal tubules, in distal convoluted tubules (DCT) and cortical collecting ducts (CCD). AGT mRNA was found in proximal tubules, descending thin limb of Henle’s loop (dTL) and in the medullary part of the thick ascending limb (mTAL). ACE mRNA was not detectable in microdissected mouse nephron segments. AT1a, AT1b and AT2 mRNA was detected in glomeruli and proximal convoluted tubules. Conclusions: Our data demonstrate a nephron-specific distribution of RAAS components. All components of the local RAAS – except ACE – are present in proximal convoluted tubules, emphasizing their involvement in sodium and water handling.

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Mouse β6 Integrin Sequence, Pattern of Expression, and Role in Kidney Development

Journal of the American Society of Nephrology ◽

10.1681/asn.v11122297 ◽

2000 ◽

Vol 11 (12) ◽

pp. 2297-2305

Author(s):

LOIS J. AREND ◽

ANN M. SMART ◽

JOSIE P. BRIGGS

Keyword(s):

Mrna Expression ◽

Reverse Transcription ◽

Kidney Development ◽

Mouse Kidney ◽

Thick Ascending Limb ◽

Integrin Expression ◽

Coding Region ◽

Embryonic Mouse ◽

Nephron Segments ◽

Reverse Transcription Pcr

Abstract. Integrins mediate cell-cell and cell-extracellular matrix interactions and play key roles in development. β6 integrin expression has been demonstrated in human fetal kidney at a higher level than in the adult, making β6 integrin a marker of interest for the study of development of the nephron. The aims of this study were to determine the cDNA sequence for the mouse β6 integrin and to characterize β6 integrin expression in the developing mouse kidney. Two embryonic mouse kidney cDNA libraries were screened, and the coding region was sequenced. The mouse β6 nucleotide coding region sequence shows 82% nucleotide identity to the human sequence. The putative amino acid sequence has 89.5% identity to human β6 integrin and contains many conserved domains. By reverse transcription-PCR, β6 integrin mRNA expression is very low at 11 d of gestation in the mouse, increases dramatically by E14 and E17 (20-fold, normalized for increases in β actin), and plateaus by 2 wk of age. β6 integrin expression is induced 15- to 20-fold after 5 d in metanephric explant culture. Reverse transcription-PCR of adult rat microdissected nephron segments demonstrates β6 integrin mRNA expression in proximal tubule, cortical thick ascending limb, distal nephron segments (inner and outer medullary collecting ducts), and macula densa—containing segments. Lectin-peroxidase and in situ colocalization studies demonstrated expression of β6 integrin mRNA in developing proximal tubules and thick ascending limb. Culture of mouse metanephric kidneys with antisense oligonucleotides to β6 integrin resulted in inhibition of ureteric bud branching and complete lack of mesenchyme condensation. These studies demonstrate a high homology between the human and mouse β6 integrin sequence, a different pattern of expression in the developing mouse kidney compared with the primate kidney, and abnormal metanephric development in culture in the absence of β6 integrin. These findings suggest an important role for β6 integrin in normal development of the mouse kidney.

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Critical role of high-mobility-group proteins in kidney development/cross-talk Wnt/β-catenin signaling pathway

American Journal of BioMedicine ◽

10.18081/2333-5106/021-01/123-134 ◽

2021 ◽

Vol 9 (1) ◽

pp. 123-134

Author(s):

Mary Ann S. Arndt ◽

William D. Wheaton

Keyword(s):

Signaling Pathway ◽

Kidney Development ◽

Critical Role ◽

High Mobility ◽

Kidney Injury ◽

High Mobility Group ◽

Loss Of Function ◽

Hmg Proteins ◽

Associated Proteins

The treatment of severe acute kidney injury with dialytic support for renal replacement therapy can be life sustaining and permit recovery from critical illness. The high-mobility-group (HMG) proteins are the most abundant non-histone chromatin-associated proteins. HMG proteins are present at high levels in various undifferentiated tissues during embryonic development and reduced in the corresponding adult tissues. We used used in study C57BL/6, HMG+/− and HMG−/− mice and found that HMG is expressed in the mouse embryonic kidney at the cortex area. HMG knockout led to enhanced Wnt/β-catenin signaling pathway. Analysis of siRNA-mediated loss-of-function experiments in embryonic kidney culture confirmed the role of HMG as a key regulator of cortex epithelium differentiation.

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Nephron progenitor maintenance is controlled through FGFs and Sprouty1 Interaction

10.1101/2020.03.26.010421 ◽

2020 ◽

Author(s):

Sung-Ho Huh ◽

Ligyeom Ha ◽

Hee-Seong Jang

Keyword(s):

Cell Death ◽

Tyrosine Kinases ◽

Kidney Development ◽

Renal Agenesis ◽

Treatment Strategies ◽

Loss Of Function ◽

Nephron Progenitors ◽

Novel Treatment Strategies ◽

Nephron Progenitor ◽

Progenitor Maintenance

AbstractThe nephron progenitor cells (NPCs) give rise to all segments of functional nephrons and are of great interest due to their potential as a source for novel treatment strategies for kidney disease. Fibroblast growth factor (FGF) signal plays pivotal roles in generating and maintaining NPCs during kidney development. However, molecule(s) regulating FGF signal during nephron development is not known. Sprouty (SPRY) is an antagonist of receptor tyrosine kinases. During kidney development, SPRY1 is expressed in the ureteric buds (UBs) and regulates UB branching by antagonizing Ret-GDNF signal. Here, we provide evidence that SPRY1 expressed in NPCs modulates activity of FGF signal in NPCs and regulates NPC stemness. Haploinsufficiency of Spry1 rescues bilateral renal agenesis and premature NPC differentiation caused by loss of Fgf9 and Fgf20. In addition, haploinsufficiency of Spry1 rescues NPC proliferation and cell death defects induced by loss of Fgf9 and Fgf20. In the absence of SPRY1, FGF9 and FGF20, another FGF ligand, FGF8 promotes nephrogenesis. Deleting both Fgf8 and Fgf20 results in kidney agenesis and defects in NPC proliferation and cell death. Rescue of loss of Fgf9 and Fgf20 induced renal agenesis by Spry1 haploinsufficiency was reversed when one copy of Fgf8 was deleted. These findings indicate the importance of the balance between positive and negative signal during NPC maintenance. Failure of the balance may underlie some human congenital kidney malformation.Significance StatementNephrons are functional units of kidney to filter blood to excrete wastes and regulate osmolarity and ion concentrations. Nephrons are derived from nephron progenitors. Nephron progenitors are depleted during kidney development which makes it unable to regenerate nephrons. Therefore, understanding signaling molecules regulating nephron progenitor generation and maintenance is of great interest for the future kidney regenerative medicine. Here, we show that Sprouty1 regulates nephron progenitor maintenance by inhibiting FGF signal. Deletion of Sprouty1 rescues renal agenesis and nephron progenitor depletion in the Fgf9/20 loss-of-function kidneys. Further decrease of FGF signal by deleting one copy of Fgf8 makes kidneys irresponsive to Sprouty1 resulting in failure of nephron progenitor maintenance. This study thus identifies the reciprocal function of FGF-Sprouty1 signal during nephron progenitor development.

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Critical role of high-mobility-group proteins in kidney development/cross-talk Wnt/β-catenin signaling pathway

American Journal of BioMedicine ◽

10.18081/2333-5106/021-01/135-144 ◽

2021 ◽

Vol 9 (1) ◽

pp. 135-144

Keyword(s):

Signaling Pathway ◽

Kidney Development ◽

Critical Role ◽

High Mobility ◽

High Mobility Group ◽

Loss Of Function ◽

Hmg Proteins ◽

Cortex Area ◽

Associated Proteins

recovery from critical illness.The high-mobility-group (HMG) proteins are the most abundant non-histone chromatin-associated proteins. HMG proteins are present at high levels in various undifferentiated tissues during embryonic development and reduced in the corresponding adult tissues. We used used in study C57BL/6, HMG+/− and HMG−/− mice and found that HMG is expressed in the mouse embryonic kidney at the cortex area. HMG knockout led to enhanced Wnt/β-catenin signaling pathway. Analysis of siRNA-mediated loss-of-function experiments in embryonic kidney culture confirmed the role of HMG as a key regulator of cortex epithelium differentiation.

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Single cell RNA sequencing uncovers cellular developmental sequences and novel potential intercellular communications in embryonic kidney

Scientific Reports ◽

10.1038/s41598-020-80154-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Isao Matsui ◽

Ayumi Matsumoto ◽

Kazunori Inoue ◽

Yusuke Katsuma ◽

Seiichi Yasuda ◽

...

Keyword(s):

Single Cell ◽

Rna Sequencing ◽

Kidney Development ◽

Developmental Process ◽

Mouse Kidney ◽

Related Factors ◽

Embryonic Mouse ◽

Nephron Progenitors ◽

Developmental Sequences ◽

Single Cell Rna Sequencing

AbstractKidney development requires the coordinated growth and differentiation of multiple cells. Despite recent single cell profiles in nephrogenesis research, tools for data analysis are rapidly developing, and offer an opportunity to gain additional insight into kidney development. In this study, single-cell RNA sequencing data obtained from embryonic mouse kidney were re-analyzed. Manifold learning based on partition-based graph-abstraction coordinated cells, reflecting their expected lineage relationships. Consequently, the coordination in combination with ForceAtlas2 enabled the inference of parietal epithelial cells of Bowman’s capsule and the inference of cells involved in the developmental process from the S-shaped body to each nephron segment. RNA velocity suggested developmental sequences of proximal tubules and podocytes. In combination with a Markov chain algorithm, RNA velocity suggested the self-renewal processes of nephron progenitors. NicheNet analyses suggested that not only cells belonging to ureteric bud and stroma, but also endothelial cells, macrophages, and pericytes may contribute to the differentiation of cells from nephron progenitors. Organ culture of embryonic mouse kidney demonstrated that nerve growth factor, one of the nephrogenesis-related factors inferred by NicheNet, contributed to mitochondrial biogenesis in developing distal tubules. These approaches suggested previously unrecognized aspects of the underlying mechanisms for kidney development.

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Parkin interacting substrate zinc finger protein 746 is a pathological mediator in Parkinson’s disease

Brain ◽

10.1093/brain/awz172 ◽

2019 ◽

Vol 142 (8) ◽

pp. 2380-2401 ◽

Cited By ~ 9

Author(s):

Saurav Brahmachari ◽

Saebom Lee ◽

Sangjune Kim ◽

Changqing Yuan ◽

Senthilkumar S Karuppagounder ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Zinc Finger ◽

Zinc Finger Protein ◽

Critical Role ◽

Trna Synthetase ◽

Loss Of Function ◽

Substrate Protein ◽

Finger Protein ◽

Sporadic Parkinson’S Disease

Abstract α-Synuclein misfolding and aggregation plays a major role in the pathogenesis of Parkinson’s disease. Although loss of function mutations in the ubiquitin ligase, parkin, cause autosomal recessive Parkinson’s disease, there is evidence that parkin is inactivated in sporadic Parkinson’s disease. Whether parkin inactivation is a driver of neurodegeneration in sporadic Parkinson’s disease or a mere spectator is unknown. Here we show that parkin in inactivated through c-Abelson kinase phosphorylation of parkin in three α-synuclein-induced models of neurodegeneration. This results in the accumulation of parkin interacting substrate protein (zinc finger protein 746) and aminoacyl tRNA synthetase complex interacting multifunctional protein 2 with increased parkin interacting substrate protein levels playing a critical role in α-synuclein-induced neurodegeneration, since knockout of parkin interacting substrate protein attenuates the degenerative process. Thus, accumulation of parkin interacting substrate protein links parkin inactivation and α-synuclein in a common pathogenic neurodegenerative pathway relevant to both sporadic and familial forms Parkinson’s disease. Thus, suppression of parkin interacting substrate protein could be a potential therapeutic strategy to halt the progression of Parkinson’s disease and related α-synucleinopathies.

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