Journal of cell science最新文献

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Human disease variants of KATNIP fail to support CILK1 activation and control of primary cilia. KATNIP的人类疾病变体不能支持CILK1的激活和对初级纤毛的控制。
IF 3.6 3区 生物学
Journal of cell science Pub Date : 2025-10-15 Epub Date: 2025-07-30 DOI: 10.1242/jcs.264056
Evan H Carpenter, Cheuk Ying Chu, Ana Limerick, David L Brautigan, Zheng Fu
{"title":"Human disease variants of KATNIP fail to support CILK1 activation and control of primary cilia.","authors":"Evan H Carpenter, Cheuk Ying Chu, Ana Limerick, David L Brautigan, Zheng Fu","doi":"10.1242/jcs.264056","DOIUrl":"10.1242/jcs.264056","url":null,"abstract":"<p><p>Pathogenic variants in KATNIP (encoding katanin-interacting protein) are linked to Joubert syndrome, a prototypical ciliopathy. KATNIP is a scaffold protein that binds and potentiates ciliogenesis-associated kinase 1 (CILK1) activation and function to control cilia length and frequency. We previously showed that of the three predicted 'domains of unknown functions' (DUFs) in KATNIP, the DUF2 domain alone supports binding to CILK1 without activating CILK1. Here, we report three human disease variants of KATNIP with different lengths that exhibit loss of function. The longest variant of KATNIP M1474C, which is truncated near the C-terminus, binds to CILK1 but does not support the activating TDY phosphorylation in CILK1, the phosphorylation of CILK1 substrates, or the restriction of cilia length and ciliation rate. Deletion analysis of KATNIP further revealed that residues 1524-1573 encompassing predicted β-sheets and an α-helix are essential for CILK1 activation and function. The results support a model where KATNIP uses separate domains to bind and to enhance activation of CILK1, enabling CILK1 function in control of cilia formation and elongation.</p>","PeriodicalId":15227,"journal":{"name":"Journal of cell science","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144575555","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Asymmetries in the three-dimensional beat of Chlamydomonas reinhardtii flagella revealed by holographic microscopy. 用全息显微镜观察莱茵衣藻鞭毛三维节奏的不对称性。
IF 3.6 3区 生物学
Journal of cell science Pub Date : 2025-10-15 Epub Date: 2025-10-02 DOI: 10.1242/jcs.263946
Laurence G Wilson, Martin A Bees
{"title":"Asymmetries in the three-dimensional beat of Chlamydomonas reinhardtii flagella revealed by holographic microscopy.","authors":"Laurence G Wilson, Martin A Bees","doi":"10.1242/jcs.263946","DOIUrl":"10.1242/jcs.263946","url":null,"abstract":"<p><p>We present the first three-dimensional time-resolved imaging of the Chlamydomonas reinhardtii flagellar waveform. This freshwater alga is a model system for eukaryotic flagella that allow cells to move and pump fluid. During the power stroke, the flagella show rotational symmetry about the centre line of the cell, but during the recovery stroke they display mirror symmetry about the same axis. Furthermore, and in contrast to the usual assumptions about beat planarity, we show a subtle rotational motion of the flagella at the initiation of the power stroke, which is mechanically rectified into a quasi-planar mode. We apply resistive force theory to infer the swimming speed and rotational speed of the cells, when a force-free configuration is approximated using a cell on a micropipette, showing good agreement with experimental results on freely swimming cells.</p>","PeriodicalId":15227,"journal":{"name":"Journal of cell science","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144873371","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
SAXO proteins mediate tubulin turnover in axonemal microtubules of Chlamydomonas. SAXO蛋白介导衣藻轴突微管中的微管蛋白转换。
IF 3.3 3区 生物学
Journal of cell science Pub Date : 2025-10-15 Epub Date: 2025-06-26 DOI: 10.1242/jcs.264074
Yongli Zhang, Xuecheng Li, Zhengmao Wang, Junmin Pan
{"title":"SAXO proteins mediate tubulin turnover in axonemal microtubules of Chlamydomonas.","authors":"Yongli Zhang, Xuecheng Li, Zhengmao Wang, Junmin Pan","doi":"10.1242/jcs.264074","DOIUrl":"10.1242/jcs.264074","url":null,"abstract":"<p><p>Cilia and eukaryotic flagella are microtubule-based organelles that are crucial for cell motility and signaling. SAXO proteins (denoted for 'stabilizers of axonemal microtubules') are found exclusively in flagellated or ciliated organisms, but their physiological functions remain unclear. We investigated four SAXO proteins (SAXO1-SAXO4) in Chlamydomonas reinhardtii, identified via bioinformatics. All localize to cilia but differ in axonemal binding and spatial distribution. Single SAXO knockouts had no effect, whereas double mutants (saxo1/2, saxo1/3 and saxo2/3) showed shorter cilia. This phenotype intensified in the saxo1/2/3 triple mutant but not further in the quadruple mutant. Ciliary beating remained normal in saxo1/2/3 mutants, even under mechanical stress, indicating that SAXO1-SAXO3 are not essential for ciliary rigidity. Biochemical and proteomic analyses revealed no significant changes in the ciliary proteome or in tubulin acetylation, tyrosination and glutamylation within cilia. However, dikaryon assays with labeled tubulin showed that there was increased axonemal tubulin turnover in saxo1/2/3 mutant. Our findings underscore a crucial role of SAXO proteins in stabilizing axonemal microtubules by reducing tubulin turnover, thereby regulating ciliary length and assembly, and provide new insights into their function in cilia.</p>","PeriodicalId":15227,"journal":{"name":"Journal of cell science","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144150414","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Renal tissue-resident macrophages promote cystogenesis in early polycystic kidney disease. 肾组织内巨噬细胞促进早期多囊肾病的膀胱形成。
IF 3.6 3区 生物学
Journal of cell science Pub Date : 2025-10-15 Epub Date: 2025-08-26 DOI: 10.1242/jcs.263992
Rudolfo Karl, Arsila Palliyulla Kariat Ashraf, Maria Francesca Viola, Katharina Hopp, Elvira Mass, Dagmar Wachten
{"title":"Renal tissue-resident macrophages promote cystogenesis in early polycystic kidney disease.","authors":"Rudolfo Karl, Arsila Palliyulla Kariat Ashraf, Maria Francesca Viola, Katharina Hopp, Elvira Mass, Dagmar Wachten","doi":"10.1242/jcs.263992","DOIUrl":"10.1242/jcs.263992","url":null,"abstract":"<p><p>Autosomal-dominant polycystic kidney disease (ADPKD) is a ciliopathy characterized by mutations in PKD1 or PKD2, which drive cystogenesis in renal epithelial cells. Immune cells, particularly macrophages, contribute to disease progression, yet their role remains incompletely understood. Here, we performed an in-depth analysis of renal macrophage ontogeny and phenotype and investigated their function in an ADPKD mouse model (Pkd1RC/RC) with adult onset and slow disease progression. We demonstrate that the numbers of tissue-resident macrophages were already increased before cyst formation. Using a flow cytometry screening panel, we further characterized the tissue-resident macrophage populations using surface markers and identified a novel marker that shows the potential to determine macrophage remodeling at different disease stages. To reveal the cellular interaction of tissue-resident macrophages and renal epithelial cells in further detail, we established a 3D co-culture system, demonstrating that tissue-resident macrophages from Pkd1RC/RC mice, isolated at a stage before cysts were observed, already showed enhanced cystogenesis in vitro. These findings underscore the crucial role of tissue-resident macrophages in ADPKD and suggest targeting epithelial cell-macrophage interactions as a promising therapeutic avenue.</p>","PeriodicalId":15227,"journal":{"name":"Journal of cell science","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12450461/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144855327","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Inhibition of Hedgehog signaling does not mitigate polycystic kidney disease severity in a Pkd1 mutant mouse model. 在Pkd1突变小鼠模型中,抑制刺猬信号传导不能减轻多囊肾病的严重程度。
IF 3.6 3区 生物学
Journal of cell science Pub Date : 2025-10-15 Epub Date: 2025-07-31 DOI: 10.1242/jcs.264133
Sean K Gombart, Scott Houghtaling, Tzu-Hua Ho, David R Beier
{"title":"Inhibition of Hedgehog signaling does not mitigate polycystic kidney disease severity in a Pkd1 mutant mouse model.","authors":"Sean K Gombart, Scott Houghtaling, Tzu-Hua Ho, David R Beier","doi":"10.1242/jcs.264133","DOIUrl":"10.1242/jcs.264133","url":null,"abstract":"<p><p>Autosomal dominant polycystic kidney disease (ADPKD) is a monogenic disorder caused by mutations in PKD1 or PKD2, encoding polycystin-1 and polycystin-2, respectively. These polycystins form a cilia-localized complex that, when mutated, fails to inhibit an uncharacterized cilia-dependent cyst activation (CDCA) signal. This leads to progressive bilateral cyst growth and ultimately compromised renal function. Previous in vitro and in vivo studies from our group have demonstrated that Hedgehog (Hh) signaling inhibition reduces renal cystic severity in PKD models. To further investigate, we inactivated several Hh pathway components (Gli1, Gli2, Gli3 and Smo) in a Pkd1 hypomorphic mouse model through conditional deletion by tamoxifen-induced Cre-Lox recombination. We assessed cystic severity using kidney weight assessment and a microcomputed tomography (micro-CT)-based 3D imaging assay. Contrary to expectations, inactivation of Gli1 and Smo significantly increased cystogenesis. These findings suggest that Hh signaling does not mediate the CDCA signal.</p>","PeriodicalId":15227,"journal":{"name":"Journal of cell science","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12377710/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144484530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Phosphorylation-induced SUMOylation promotes Ulk4 condensation at the ciliary tip to transduce Hedgehog signal. 磷酸化诱导的SUMOylation促进Ulk4在纤毛尖端的缩聚,从而转导Hedgehog信号。
IF 3.3 3区 生物学
Journal of cell science Pub Date : 2025-10-15 Epub Date: 2025-05-19 DOI: 10.1242/jcs.263695
Mengmeng Zhou, Yuhong Han, Jin Jiang
{"title":"Phosphorylation-induced SUMOylation promotes Ulk4 condensation at the ciliary tip to transduce Hedgehog signal.","authors":"Mengmeng Zhou, Yuhong Han, Jin Jiang","doi":"10.1242/jcs.263695","DOIUrl":"10.1242/jcs.263695","url":null,"abstract":"<p><p>Hedgehog (Hh) signaling controls embryonic development and adult tissue homeostasis through the Gli family of transcription factors. In vertebrates, Hh signal transduction depends on the primary cilium, where Gli proteins are thought to be activated at the ciliary tip, but the underlying mechanism has remained poorly understood. Here, we provide evidence that two Unc-51-like kinase (Ulk) family members, Stk36 and Ulk4, regulate Gli2 ciliary tip localization and activation through phosphorylation and SUMOylation-mediated condensation in response to the Hh family protein Shh. We find that Stk36-mediated phosphorylation of Ulk4 promotes its SUMOylation in response to Shh, and the subsequent interaction between SUMO and a SUMO-interacting-motif (SIM) in the C-terminal region of Ulk4 drives Ulk4 self-assembly to form biomolecular condensates that also recruit Stk36 and Gli2. SUMOylation or SIM-deficient Ulk4 failed to accumulate at ciliary tip to activate Gli2 whereas phospho-mimetic mutation of Ulk4 sufficed to drive Ulk4, Stk36 and Gli2 condensation at ciliary tip, leading to constitutive Shh pathway activation in a manner dependent on Ulk4 SUMOylation. Taken together, our results suggest that phosphorylation-dependent SUMOylation of Ulk4 promotes kinase-substrate condensation at ciliary tip to transduce the Hh signal.</p>","PeriodicalId":15227,"journal":{"name":"Journal of cell science","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12148026/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143764075","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Skeletal ciliopathy variants of the dynein-2 DYNC2LI1 subunit impair osteogenic differentiation of mesenchymal stem cells. 骨骼肌纤毛病动力蛋白-2 DYNC2LI1亚基变异损害间充质干细胞的成骨分化。
IF 3.3 3区 生物学
Journal of cell science Pub Date : 2025-10-15 Epub Date: 2025-06-20 DOI: 10.1242/jcs.263737
Yamato Ishida, Haruka Hoshi, Kenichi Kawano, Hye-Won Shin, Yohei Katoh, Kazuhisa Nakayama
{"title":"Skeletal ciliopathy variants of the dynein-2 DYNC2LI1 subunit impair osteogenic differentiation of mesenchymal stem cells.","authors":"Yamato Ishida, Haruka Hoshi, Kenichi Kawano, Hye-Won Shin, Yohei Katoh, Kazuhisa Nakayama","doi":"10.1242/jcs.263737","DOIUrl":"10.1242/jcs.263737","url":null,"abstract":"<p><p>Skeletal ciliopathies result from defects in primary cilia, which are crucial for embryonic development because they transduce extracellular signals, including Hedgehog. Selective transport of ciliary proteins is mediated by the intraflagellar transport (IFT) machinery, containing the IFT-A and IFT-B complexes and the kinesin-2 and dynein-2 motors. Biallelic loss-of-function variants in genes encoding dynein-2-specific subunits, including DYNC2LI1, cause skeletal ciliopathies. As mesenchymal stem cells (MSCs) differentiate into osteoblasts, we investigated the effects of pathogenic variants of DYNC2LI1 on osteogenic differentiation of the MSC-like line C3H10T1/2. Dync2li1-knockout cells expressing disease-causing DYNC2LI1 variants demonstrated defects in the retrograde ciliary protein trafficking, including Hedgehog pathway GPCRs, Smoothened and GPR161. Furthermore, Dync2li1-knockout cells expressing the pathogenic variants demonstrated impaired Hedgehog signaling, in particular, a reduced ratio of the GLI3 repressor form to total GLI3, resulting in impaired osteogenic differentiation of MSCs. By contrast, osteogenic differentiation via BMP signaling was derepressed in Dync2li1-knockout cells. This suggests that skeletal ciliopathies caused by DYNC2LI1 variants could be attributable in part to impaired osteogenic differentiation due to defects in Hedgehog signaling, resulting from defects in retrograde ciliary protein trafficking.</p>","PeriodicalId":15227,"journal":{"name":"Journal of cell science","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144110669","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Three-dimensional beating pattern of the ciliary tip in the live ciliate Tetrahymena. 活体纤毛四膜虫纤毛尖端的三维跳动模式。
IF 3.6 3区 生物学
Journal of cell science Pub Date : 2025-10-15 Epub Date: 2025-09-24 DOI: 10.1242/jcs.264027
Akisato Marumo, Hiroto Ishii, Shin Yamaguchi, Rieko Sumiyoshi, Kyohei Matsuda, Masahiko Yamagishi, Junichiro Yajima
{"title":"Three-dimensional beating pattern of the ciliary tip in the live ciliate Tetrahymena.","authors":"Akisato Marumo, Hiroto Ishii, Shin Yamaguchi, Rieko Sumiyoshi, Kyohei Matsuda, Masahiko Yamagishi, Junichiro Yajima","doi":"10.1242/jcs.264027","DOIUrl":"10.1242/jcs.264027","url":null,"abstract":"<p><p>Ciliates utilise motile cilia, which are highly dynamic organelles protruding from the cell surface, to swim helically in a three-dimensional (3D) space. The 3D nature of their swimming behaviour and rapid ciliary beatings make its quantitative analysis difficult. Here, we quantified the 3D motion of a microbead bound to a ciliary tip in a live immobilised Tetrahymena thermophila cell using 3D tracking optical microscopy. We found that the tip of individual ciliate cilia, consisting of the 9+2 structure of the axoneme, shows semicircular counterclockwise rotation in a single plane when looking down on the cilium. The rotational trajectories of the tip consist of fast and slow strokes, with the tip path during the fast and slow strokes being an arc and linear, respectively. The direction of the fast stroke of the ciliary tip, with respect to the cell body, was from the right-anterior to the left-posterior region, which is consistent with the direction that would induce right-handed helical swimming of the Tetrahymena.</p>","PeriodicalId":15227,"journal":{"name":"Journal of cell science","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144955487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
β-Arrestin mediates the export of ciliary GPR161 but not Smoothened together with the BBSome and intraflagellar transport machinery. β- arrest介导睫状GPR161的输出,但不与BBSome和IFT机制一起平滑。
IF 3.3 3区 生物学
Journal of cell science Pub Date : 2025-10-15 Epub Date: 2025-06-20 DOI: 10.1242/jcs.263793
Taiju Fujii, Norihito Murai, Shinya Aso, Hiroyuki Takatsu, Hye-Won Shin, Yohei Katoh, Kazuhisa Nakayama
{"title":"β-Arrestin mediates the export of ciliary GPR161 but not Smoothened together with the BBSome and intraflagellar transport machinery.","authors":"Taiju Fujii, Norihito Murai, Shinya Aso, Hiroyuki Takatsu, Hye-Won Shin, Yohei Katoh, Kazuhisa Nakayama","doi":"10.1242/jcs.263793","DOIUrl":"10.1242/jcs.263793","url":null,"abstract":"<p><p>Specific G-protein-coupled receptors (GPCRs) exist on the ciliary membrane. Hedgehog signaling activation triggers the import of Smoothened into and export of GPR161 from cilia. The BBSome, which comprises eight Bardet-Biedl syndrome (BBS) proteins, mediates GPCR export, together with the intraflagellar transport (IFT) machinery, containing the IFT-A and IFT-B complexes. The absence of any BBSome subunit or IFT27 (also known as BBS19) (an IFT-B subunit) impairs ciliary GPCR export, including that of GPR161. Plasma membrane GPCRs undergo phosphorylation by GPCR kinases (GRKs) and subsequent binding of β-arrestins [β-arrestin1 (ARRB1) and β-arrestin2 (ARRB2)], which is crucial for clathrin-mediated endocytosis. We here confirmed that GPR161 and β-arrestin are accumulated within cilia in the absence of IFT27 or the BBSome, and that ARRB1 and ARRB2 double-knockout impairs GPR161 export. Notably, we found that activation-mimetic β-arrestin mutants can interact with both the BBSome and ciliary GPCRs, and cause constitutive export of GPR161. Moreover, we demonstrated that GRK2 plays a crucial role in GPR161 export. We here propose that phosphorylated GPR161 recruits β-arrestins, converting them into their activated conformation. Activated β-arrestins then interact with the BBSome, which connects them to the IFT machinery to facilitate GPR161 export.</p>","PeriodicalId":15227,"journal":{"name":"Journal of cell science","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144093707","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Urinary renal epithelial cells can be used for NPHP1 phenotyping and a personalized therapeutic strategy. 尿肾上皮细胞的NPHP1表型和个性化治疗反应。
IF 3.6 3区 生物学
Journal of cell science Pub Date : 2025-10-15 Epub Date: 2025-09-08 DOI: 10.1242/jcs.264141
Praveen Dhondurao Sudhindar, Eric Olinger, Zachary T Sentell, Holly Mabillard, Barbora Dicka, Katrina Wood, Dominic Rutland, Catherine Collins, Marco Trevisan-Herraz, John A Sayer, Juliana E Arcila-Galvis
{"title":"Urinary renal epithelial cells can be used for NPHP1 phenotyping and a personalized therapeutic strategy.","authors":"Praveen Dhondurao Sudhindar, Eric Olinger, Zachary T Sentell, Holly Mabillard, Barbora Dicka, Katrina Wood, Dominic Rutland, Catherine Collins, Marco Trevisan-Herraz, John A Sayer, Juliana E Arcila-Galvis","doi":"10.1242/jcs.264141","DOIUrl":"10.1242/jcs.264141","url":null,"abstract":"<p><p>Nephronophthisis (NPHP) is a recessive tubulointerstitial nephropathy and a leading genetic cause of kidney failure in children and young adults. The most common genetic cause is a homozygous deletion of NPHP1, which encodes nephrocystin-1, a protein essential for primary cilium structure and cell junctions. Using personalized medicine and deep phenotyping, we investigated a family with three siblings carrying a homozygous NPHP1 deletion. We compared kidney biopsy tissue and human urine-derived renal epithelial cells (hURECs) from these individuals. Bulk RNA-seq on patient hURECs revealed altered expression in EGFR signalling, extracellular components and adherens junctions, which is consistent with the known roles for nephrocystin-1. Treatment with alprostadil, a proposed NPHP therapy, increased ciliation but worsened ciliary elongation. By contrast, the EGFR kinase inhibitor AG556 rescued of ciliary length and morphology. Transcriptional profiling post-treatment showed AG556 reversed the disease signature more effectively that alprostadil. These findings suggest that EGFR inhibition might offer a more promising therapeutic strategy for NPHP1-associated renal ciliopathy, warranting further testing in in vivo models before clinical application.</p>","PeriodicalId":15227,"journal":{"name":"Journal of cell science","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12450468/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144799207","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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