bims-bicyki Biomed News
on Bicaudal-C1 and interactors in cystic kidney disease
Issue of 2021‒05‒16
fifteen papers selected by
Céline Gagnieux
École Polytechnique Fédérale de Lausanne (EPFL)
  1. Inward calcium current through the polycystin-2-dependent channels of renal primary cilia.
  2. Rab34 is necessary for early stages of intracellular ciliogenesis.
  3. Successful endoscopic surgery for emphysematous pyelonephritis in a non-diabetic patient with autosomal dominant polycystic kidney disease: A case report.
  4. Spontaneous coronary dissection should not be ignored in patients with chest pain in autosomal dominant polycystic kidney disease: A case report.
  5. Applications of Herbal Medicine to Treat Autosomal Dominant Polycystic Kidney Disease.
  6. Regional Variations in Prevalence and Severity of Autosomal Dominant Polycystic Kidney Disease in the United States.
  7. Cinacalcet may suppress kidney enlargement in hemodialysis patients with autosomal dominant polycystic kidney disease.
  8. Primary cilia control endothelial permeability by regulating expression and location of junction proteins.
  9. Rab34 GTPase mediates ciliary membrane formation in the intracellular ciliogenesis pathway.
  10. ARP-T1-associated Bazex-Dupré-Christol syndrome is an inherited basal cell cancer with ciliary defects characteristic of ciliopathies.
  11. Odontoblast differentiation is regulated by an interplay between primary cilia and the canonical Wnt pathway.
  12. Primary cilia: turning points in establishing their ubiquity, sensory role and the pathological consequences of dysfunction.
  13. TRIM37 prevents formation of condensate-organized ectopic spindle poles to ensure mitotic fidelity.
  14. Regulation and mechanism of YAP/TAZ in the mechanical microenvironment of stem cells (Review).
  15. Control of multiciliogenesis by miR-34/449 in the male reproductive tract through enforcing cell cycle exit.
  1. Am J Physiol Renal Physiol. 2021 May 10.
    Inward calcium current through the polycystin-2-dependent channels of renal primary cilia.
    Steven J Kleene, Nancy K Kleene.
      In 15% of cases, autosomal dominant polycystic kidney disease (ADPKD) arises from defects in polycystin-2 (PC2). PC2 is a member of the TRPP subfamily of cation-conducting channels and is expressed in the endoplasmic reticulum and primary cilium of renal epithelial cells. PC2 opposes a pro-cystogenic influence of the cilium, and it has been proposed that this beneficial effect is mediated in part by a flow of Ca2+ through PC2 channels into the primary cilium. However, previous efforts to determine the permeability of PC2 channels to Ca2+ have yielded widely varying results. Here we report the mean macroscopic Ca2+ influx through native PC2 channels in the primary cilia of mIMCD-3 cells, which are derived from murine inner medullary collecting duct. Under conditions designed to isolate inward Ca2+ currents, a small inward Ca2+ current was detected in cilia with active PC2 channels, but not in cilia lacking those channels. The current was activated by addition of 10 µM internal Ca2+, which is known to activate ciliary PC2 channels. It was blocked by 10 µM isosakuranetin, which blocks the same channels. On average, the current amplitude was -1.8 pA at -190 mV; its conductance from -50 to -200 mV averaged 20 pS. Thus the native PC2 channels of renal primary cilium are able to conduct a small but detectable Ca2+ influx under the conditions tested. The possible consequences of this influx are discussed.
    Keywords:  PKD2; TRPP; polycystic kidney disease; polycystin-2; primary cilium
    DOI:  https://doi.org/10.1152/ajprenal.00062.2021
  2. Curr Biol. 2021 May 07. pii: S0960-9822(21)00531-5. [Epub ahead of print]
    Rab34 is necessary for early stages of intracellular ciliogenesis.
    Michael W Stuck, Weng Man Chong, Jung-Chi Liao, Gregory J Pazour.
      Primary cilia are sensory organelles present on most vertebrate cells and are critical for development and health. Ciliary dysfunction is associated with a large class of human pathologies collectively known as ciliopathies. These include cystic kidneys, blindness, obesity, skeletal malformations, and other organ anomalies. Using a proximity biotinylation with Ift27 as bait, we identified the small guanosine triphosphatase (GTPase) Rab34 as a ciliary protein. Rab34 localizes to the centrosomes near the mother centriole, the axoneme of developed cilia, and highly dynamic tubule structures in the centrosomal region. Rab34 is required for cilia formation in fibroblasts, where we find that Rab34 loss blocks ciliogenesis at an early step of ciliary vesicle formation. In inner medullary collecting duct (IMCD3) epithelial cells, the requirement is more complex, with Rab34 needed in cells grown at low density but becoming less important as cell density increases. Ciliogenesis can proceed by an internal pathway where cilia form in the cytoplasm before being displayed on the ciliary surface or cilia can assemble by an external pathway where the centriole docks on the plasma membrane before ciliary assembly. Fibroblasts are thought to use the internal pathway, although IMCD3 cells are thought to use the external pathway. However, we find that IMCD3 cells can use the internal assembly pathway and significant numbers of internally assembling cilia are observed in low-density cells. Together, our work indicates that Rab34 is required for internal assembly of cilia, but not for cilia built on the cell surface.
    Keywords:  Hedgehog signaling; cilia; intraflagellar transport; smoothened
    DOI:  https://doi.org/10.1016/j.cub.2021.04.018
  3. World J Clin Cases. 2021 Apr 26. 9(12): 2862-2867
    Successful endoscopic surgery for emphysematous pyelonephritis in a non-diabetic patient with autosomal dominant polycystic kidney disease: A case report.
    Yi Jiang, Richard Lo, Zhen-Quan Lu, Xiao-Bao Cheng, Lin Xiong, Bing-Feng Luo.
      BACKGROUND: Emphysema pyelonephritis (EPN) is a very dangerous type of urinary tract infection. It is a lethal disease that develops rapidly and causes the patient to deteriorate rapidly, and it can easily lead to systemic infections and even sepsis. The incidence is extremely low, and it is prevalent in patients with diabetes. We here report a case of EPN in a non-diabetic patient with autosomal dominant polycystic kidney disease (ADPKD). We share the diagnosis and treatment procedure for this extremely rare condition to make this disease easier to identify and address early.CASE SUMMARY: A 47-year-old woman presented to the emergency department of our hospital with a high fever and left back pain lasting 4 d. She had a history of autosomal dominant polycystic kidney and polycystic liver. She was diagnosed with left type I EPN and her vital signs deteriorated so quickly that she underwent an emergency operation in which a D-J tube was inserted into her left ureter on the second day after admission. Two months later, she underwent a second-stage flexible ureteroscopy and lithotripsy. Despite postoperative sepsis, she finally recovered after active symptomatic support treatment and effective anti-infective treatment.
    CONCLUSION: Although EPN is more likely to occur in diabetic patients, for non-diabetic patients with ADPKD and upper urinary tract obstruction, the disease also causes rapid deterioration. Early and accurate diagnosis and timely removal of the obstruction by invasive means may be able to save the damaged kidney and the patient's life.
    Keywords:  Autosomal dominant polycystic kidney disease; Case report; Emphysematous pyelonephritis; Endoscopic surgery; Flexible ureteroscopy lithotripsy; Lithotripsy; Necrotizing infection
    DOI:  https://doi.org/10.12998/wjcc.v9.i12.2862
  4. World J Clin Cases. 2021 May 06. 9(13): 3095-3101
    Spontaneous coronary dissection should not be ignored in patients with chest pain in autosomal dominant polycystic kidney disease: A case report.
    Jun Qian, Yan Lai, Li-Jun Kuang, Fei Chen, Xue-Bo Liu.
      BACKGROUND: When autosomal dominant polycystic kidney disease (ADPKD) presents with acute coronary syndrome (ACS), the possibility of spontaneous coronary artery dissection (SCAD) should be highly considered. In some cases, SCAD is considered an extrarenal manifestation of ADPKD depending on the pathological characteristics of the unstable arterial wall in ADPKD.CASE SUMMARY: Here, we report a 46-year-old female patient with ADPKD who presented with ACS. Coronary angiography revealed no definite signs of dissection, while intravascular ultrasound revealed a proximal to distal dissection of the left circumflex. After a careful conservative medication treatment, the patient exhibited favorable prognosis.
    CONCLUSION: In cases of ADPKD co-existing with ACS, differential diagnosis of SCAD should be considered. Moreover, when no clear dissection is found on coronary angiography, IVUS should be performed to prevent missed diagnosis.
    Keywords:  Autosomal dominant polycystic kidney disease; Case report; Intravascular ultrasound; Spontaneous coronary artery dissection
    DOI:  https://doi.org/10.12998/wjcc.v9.i13.3095
  5. Front Pharmacol. 2021 ;12 629848
    Applications of Herbal Medicine to Treat Autosomal Dominant Polycystic Kidney Disease.
    Guangying Shao, Shuai Zhu, Baoxue Yang.
      Autosomal dominant polycystic kidney disease (ADPKD) is a common hereditary kidney disease, which is featured by progressively enlarged bilateral fluid-filled cysts. Enlarging cysts destroy the structure of nephrons, ultimately resulting in the loss of renal function. Eventually, ADPKD develops into end-stage renal disease (ESRD). Currently, there is no effective drug therapy that can be safely used clinically. Patients progressed into ESRD usually require hemodialysis and kidney transplant, which is a heavy burden on both patients and society. Therefore, looking for effective therapeutic drugs is important for treating ADPKD. In previous studies, herbal medicines showed their great effects in multiple diseases, such as cancer, diabetes and mental disorders, which also might play a role in ADPKD treatment. Currently, several studies have reported that the compounds from herbal medicines, such as triptolide, curcumin, ginkolide B, steviol, G. lucidum triterpenoids, Celastrol, saikosaponin-d, Sparganum stoloniferum Buch.-Ham and Cordyceps sinensis, contribute to the inhibition of the development of renal cysts and the progression of ADPKD, which function by similar or different mechanisms. These studies suggest that herbal medicines could be a promising type of drugs and can provide new inspiration for clinical therapeutic strategy for ADPKD. This review summarizes the pharmacological effects of the herbal medicines on ADPKD progression and their underlying mechanisms in both in vivo and in vitro ADPKD models.
    Keywords:  autosomal dominant polycystic kidney disease (ADPKD); chronic kidney disease (CKD); herbal medicine; pathogenesis; therapy
    DOI:  https://doi.org/10.3389/fphar.2021.629848
  6. Curr Med Res Opin. 2021 May 10. 1
    Regional Variations in Prevalence and Severity of Autosomal Dominant Polycystic Kidney Disease in the United States.
    Cynthia Willey, Marjolaine Gauthier-Loiselle, Martin Cloutier, Sherry Shi, Jessica Maitland, Robert Stellhorn, Myrlene Sanon Aigbogun.
      OBJECTIVES: To evaluate geographic variation in the prevalence of autosomal dominant polycystic kidney disease (ADPKD) in the US, including ADPKD at risk of rapid progression.METHODS: Claims data from the IBM® MarketScan® Commercial and Medicare Supplemental databases (01/16/2016-12/31/2017) were used to estimate the 2017 annual and 2016-2017 two-year prevalence of diagnosed ADPKD and ADPKD at risk of rapid progression in the US overall, and stratified by census regions and states. Risk of rapid progression was identified based on either: hypertension <35 years, hematuria <30 years, albuminuria, stage 2 chronic kidney disease (CKD) <30 years, stage 3 CKD <50 years, and stage 4/5 CKD or kidney transplant <55 years.
    RESULTS: Annual prevalence was estimated at 2.34 and two-year prevalence at 3.61 per 10,000 in the US. Across census regions, two-year prevalence per 10,000 was highest in the Northeast (4.14) and lowest in the West (3.35). Prevalence was significantly correlated with the proportion of individuals in urban areas (r = 0.34, one-sided p = 0.026). In 2017, 37.5% of patients were identified as being at risk for rapid progression, and this proportion was larger among patients in the South (42.1%, p < 0.001).
    CONCLUSION: This estimate for ADPKD prevalence is consistent with previously reported national estimates, with regional variation suggesting that ADPKD might be under-diagnosed in rural areas with more limited access to care. More than one-third of ADPKD patients presented risk factors associated with rapid progression, highlighting the need for timely identification, as disease-modifying therapy may delay progression to end-stage renal disease.
    Keywords:  United States; autosomal dominant polycystic kidney disease; prevalence; regional variation
    DOI:  https://doi.org/10.1080/03007995.2021.1927690
  7. Sci Rep. 2021 May 11. 11(1): 10014
    Cinacalcet may suppress kidney enlargement in hemodialysis patients with autosomal dominant polycystic kidney disease.
    Shinya Nakatani, Kozo Nishide, Senji Okuno, Eiji Ishimura, Daijiro Kabata, Fumiyuki Morioka, Yuri Machiba, Hideki Uedono, Akihiro Tsuda, Shigeichi Shoji, Masaaki Inaba, Katsuhito Mori, Tomoyuki Yamakawa, Masanori Emoto.
      A massively enlarged kidney can impact quality of life of autosomal dominant polycystic kidney disease (ADPKD) patients. A recent in vitro study demonstrated that an allosteric modulator of the calcium sensing receptor decreases adenosine-3',5'-cyclic monophosphate, an important factor for kidney enlargement in ADPKD. Therefore, the present study was performed to determine whether cinacalcet, a calcium sensing receptor agonist, suppresses kidney enlargement in hemodialysis patients with ADPKD. Alteration of total kidney volume together with clinical parameters was retrospectively examined in 12 hemodialysis patients with ADPKD treated at a single institution in Japan. In the non-cinacalcet group with longer hemodialysis duration (n = 5), total kidney volume had an annual increase of 4.19 ± 1.71% during an overall period of 877 ± 494 days. In contrast, the annual rate of increase in total kidney volume in the cinacalcet group (n = 7) was significantly suppressed after cinacalcet treatment, from 3.26 ± 2.87% during a period of 734 ± 352 days before the start of cinacalcet to - 4.71 ± 6.42% during 918 ± 524 days after initiation of treatment (p = 0.047). The present findings showed that cinacalcet could be a novel therapeutic tool for suppression of kidney enlargement in hemodialysis patients with ADPKD.
    DOI:  https://doi.org/10.1038/s41598-021-89480-1
  8. Cardiovasc Res. 2021 May 11. pii: cvab165. [Epub ahead of print]
    Primary cilia control endothelial permeability by regulating expression and location of junction proteins.
    Mannekomba R Diagbouga, Sandrine Morel, Anne F Cayron, Julien Haemmerli, Marc Georges, Beerend P Hierck, E Allémann, Sylvain Lemeille, Philippe Bijlenga, Brenda R Kwak.
      AIMS: Wall shear stress (WSS) determines intracranial aneurysm (IA) development. Polycystic kidney disease (PKD) patients have a high IA incidence and risk of rupture. Dysfunction/absence of primary cilia in PKD endothelial cells (ECs) may impair mechano-transduction of WSS and favour vascular disorders. The molecular links between primary cilia dysfunction and IAs are unknown.METHODS AND RESULTS: Wild-type and primary cilia-deficient Tg737orpk/orpk arterial ECs were submitted to physiological (30 dynes/cm2) or aneurysmal (2 dynes/cm2) WSS and unbiased transcriptomics were performed. Tg737orpk/orpk ECs displayed a 5-fold increase in the number of WSS-responsive genes compared to wild-type cells. Moreover, we observed a lower trans-endothelial resistance and a higher endothelial permeability, which correlated with disorganized intercellular junctions in Tg737orpk/orpk cells. We identified ZO-1 as a central regulator of primary cilia-dependent endothelial junction integrity. Finally, clinical and histological characteristics of IAs from non-PKD and PKD patients were analysed. IAs in PKD patients were more frequently located in the middle cerebral artery (MCA) territory than in non-PKD patients. IA domes from the MCA of PKD patients appeared thinner with less collagen and reduced endothelial ZO-1 compared with IA domes from non-PKD patients.
    CONCLUSION: Primary cilia dampen the endothelial response to aneurysmal low WSS. In absence of primary cilia, ZO-1 expression levels are reduced, which disorganizes intercellular junctions resulting in increased endothelial permeability. This altered endothelial function may not only contribute to the severity of IA disease observed in PKD patients, but may also serve as a potential diagnostic tool to determine the vulnerability of IAs.
    Keywords:  endothelial permeability; intercellular junctions; intracranial aneurysm; primary cilium; wall shear stress
    DOI:  https://doi.org/10.1093/cvr/cvab165
  9. Curr Biol. 2021 May 08. pii: S0960-9822(21)00622-9. [Epub ahead of print]
    Rab34 GTPase mediates ciliary membrane formation in the intracellular ciliogenesis pathway.
    Anil Kumar Ganga, Margaret C Kennedy, Mai E Oguchi, Shawn Gray, Kendall E Oliver, Tracy A Knight, Enrique M De La Cruz, Yuta Homma, Mitsunori Fukuda, David K Breslow.
      The primary cilium is an essential organizing center for signal transduction, and ciliary defects cause congenital disorders known collectively as ciliopathies.1-3 Primary cilia form by two pathways that are employed in a cell-type- and tissue-specific manner: an extracellular pathway in which the cilium grows out from the cell surface and an intracellular pathway in which the nascent cilium first forms inside the cell.4-8 After exposure to the external environment, cilia formed via the intracellular pathway may have distinct functional properties, as they often remain recessed within a ciliary pocket.9,10 However, the precise mechanism of intracellular ciliogenesis and its relatedness to extracellular ciliogenesis remain poorly understood. Here we show that Rab34, a poorly characterized GTPase recently linked to cilia,11-13 is a selective mediator of intracellular ciliogenesis. We find that Rab34 is required for formation of the ciliary vesicle at the mother centriole and that Rab34 marks the ciliary sheath, a unique sub-domain of assembling intracellular cilia. Rab34 activity is modulated by divergent residues within its GTPase domain, and ciliogenesis requires GTP binding and turnover by Rab34. Because Rab34 is found on assembly intermediates that are unique to intracellular ciliogenesis, we tested its role in the extracellular pathway used by polarized MDCK cells. Consistent with Rab34 acting specifically in the intracellular pathway, MDCK cells ciliate independently of Rab34 and its paralog Rab36. Together, these findings establish that different modes of ciliogenesis have distinct molecular requirements and reveal Rab34 as a new GTPase mediator of ciliary membrane biogenesis.
    Keywords:  GTPase; Rab; centriole; cilia; ciliary vesicle; ciliogenesis; ciliopathy; membrane
    DOI:  https://doi.org/10.1016/j.cub.2021.04.075
  10. Commun Biol. 2021 May 10. 4(1): 544
    ARP-T1-associated Bazex-Dupré-Christol syndrome is an inherited basal cell cancer with ciliary defects characteristic of ciliopathies.
    Hyun-Sook Park, Eirini Papanastasi, Gabriela Blanchard, Elena Chiticariu, Daniel Bachmann, Markus Plomann, Fanny Morice-Picard, Pierre Vabres, Asma Smahi, Marcel Huber, Christine Pich, Daniel Hohl.
      Actin-Related Protein-Testis1 (ARP-T1)/ACTRT1 gene mutations cause the Bazex-Dupré-Christol Syndrome (BDCS) characterized by follicular atrophoderma, hypotrichosis, and basal cell cancer. Here, we report an ARP-T1 interactome (PXD016557) that includes proteins involved in ciliogenesis, endosomal recycling, and septin ring formation. In agreement, ARP-T1 localizes to the midbody during cytokinesis and the basal body of primary cilia in interphase. Tissue samples from ARP-T1-associated BDCS patients have reduced ciliary length. The severity of the shortened cilia significantly correlates with the ARP-T1 levels, which was further validated by ACTRT1 knockdown in culture cells. Thus, we propose that ARP-T1 participates in the regulation of cilia length and that ARP-T1-associated BDCS is a case of skin cancer with ciliopathy characteristics.
    DOI:  https://doi.org/10.1038/s42003-021-02054-9
  11. Bone. 2021 May 08. pii: S8756-3282(21)00163-0. [Epub ahead of print] 116001
    Odontoblast differentiation is regulated by an interplay between primary cilia and the canonical Wnt pathway.
    Kazumi Kawata, Keishi Narita, Ayako Washio, Chiaki Kitamura, Tatsuji Nishihara, Satoshi Kubota, Sen Takeda.
      Primary cilium is a protruding cellular organelle that has various physiological functions, especially in sensory reception. While an avalanche of reports on primary cilia have been published, the function of primary cilia in dental cells remains to be investigated. In this study, we focused on the function of primary cilia in dentin-producing odontoblasts. Odontoblasts, like most other cell types, possess primary cilia, which disappear upon the knockdown of intraflagellar transport-88. In cilia-depleted cells, the expression of dentin sialoprotein, an odontoblastic marker, was elevated, while the deposition of minerals was slowed. This was recapitulated by the activation of canonical Wnt pathway, also decreased the ratio of ciliated cells. In dental pulp cells, as they differentiated into odontoblasts, the ratio of ciliated cells was increased, whereas the canonical Wnt signaling activity was repressed. Our results collectively underscore the roles of primary cilia in regulating odontoblastic differentiation through canonical Wnt signaling. This study implies the existence of a feedback loop between primary cilia and the canonical Wnt pathway.
    Keywords:  Canonical Wnt/β-catenin signaling pathway; IFT88; Odontoblast; Odontoblast differentiation; Primary cilia
    DOI:  https://doi.org/10.1016/j.bone.2021.116001
  12. J Cell Commun Signal. 2021 May 10.
    Primary cilia: turning points in establishing their ubiquity, sensory role and the pathological consequences of dysfunction.
    Denys N Wheatley.
      For over 20 years it has finally become accepted that primary cilia are without doubt important cellular organelles, involved in signalling both intrinsically and extrinsically. The consequences of their agenesis, incorrect assembly and dysfunction only began to be fully appreciated after 2000, although this had been demonstrable over the previous two decades. Before 1980, biologists at large thought the organelle rudimentary or vestigial; how a well-developed cilium could be so slated beggars belief. Many pathological conditions have implicated the primary cilium as either a major or contributing factor, ranging from kidney malfunction (e.g. polycystic kidney disease) to mental aberrations. However, the questions of how the recognition of their prevalence, their sensory function, and their pathological involvement finally emerged as substantiated and verifiable facts needs to be addressed because what happened before the 1980s, and then notably between 1980 and 2000, can help guide research towards answering further questions on these issues. Here the intention is to focus on the salient findings (the turning points) that brought about changes in our knowledge of primary cilia. The literature on them is growing fast, with the total moving towards 20,000 reports, of which > 60% have been published in the last decade. PubMed indicates that nearly 1000 papers were published in 2020 alone. We also have to appreciate that the primary cilium can assume many different forms, each of which means that there must be many genes responsible for their development and final structure. This also suggests that there are many more functions than are currently known in both their sensory reception and signalling properties, probably for many highly specialised purposes. Malfunctioning in any of these roles will undoubtedly uncover further pathological conditions.
    DOI:  https://doi.org/10.1007/s12079-021-00615-5
  13. J Cell Biol. 2021 Jul 05. pii: e202010180. [Epub ahead of print]220(7):
    TRIM37 prevents formation of condensate-organized ectopic spindle poles to ensure mitotic fidelity.
    Franz Meitinger, Dong Kong, Midori Ohta, Arshad Desai, Karen Oegema, Jadranka Loncarek.
      Centrosomes are composed of a centriolar core surrounded by pericentriolar material that nucleates microtubules. The ubiquitin ligase TRIM37 localizes to centrosomes, but its centrosomal roles are not yet defined. We show that TRIM37 does not control centriole duplication, structure, or the ability of centrioles to form cilia but instead prevents assembly of an ectopic centrobin-scaffolded structured condensate that forms by budding off of centrosomes. In ∼25% of TRIM37-deficient cells, the condensate organizes an ectopic spindle pole, recruiting other centrosomal proteins and acquiring microtubule nucleation capacity during mitotic entry. Ectopic spindle pole-associated transient multipolarity and multipolar segregation in TRIM37-deficient cells are suppressed by removing centrobin, which interacts with and is ubiquitinated by TRIM37. Thus, TRIM37 ensures accurate chromosome segregation by preventing the formation of centrobin-scaffolded condensates that organize ectopic spindle poles. Mutations in TRIM37 cause the disorder mulibrey nanism, and patient-derived cells harbor centrobin condensate-organized ectopic poles, leading us to propose that chromosome missegregation is a pathological mechanism in this disorder.
    DOI:  https://doi.org/10.1083/jcb.202010180
  14. Mol Med Rep. 2021 Jul;pii: 506. [Epub ahead of print]24(1):
    Regulation and mechanism of YAP/TAZ in the mechanical microenvironment of stem cells (Review).
    Ying Li, Jinming Wang, Weiliang Zhong.
      Stem cells receive cues from their physical and mechanical microenvironment via mechanosensing and mechanotransduction. These cues affect proliferation, self‑renewal and differentiation into specific cell fates. A growing body of evidence suggests that yes‑associated protein (YAP) and transcriptional coactivator with PDZ‑binding motif (TAZ) mechanotransduction is key for driving stem cell behavior and regeneration via the Hippo and other signaling pathways. YAP/TAZ receive a range of physical cues, including extracellular matrix stiffness, cell geometry, flow shear stress and mechanical forces in the cytoskeleton, and translate them into cell‑specific transcriptional programs. However, the mechanism by which mechanical signals regulate YAP/TAZ activity in stem cells is not fully understand. The present review summarizes the current knowledge of the mechanisms involved in YAP/TAZ regulation on the physical and mechanical microenvironment, as well as its potential effects on stem cell differentiation.
    Keywords:  mechanotransduction; microenvironment; signaling pathway; stem cells; yes‑associated protein/transcriptional coactivator with PDZ‑binding motif
    DOI:  https://doi.org/10.3892/mmr.2021.12145
  15. J Cell Sci. 2021 May 01. pii: jcs253450. [Epub ahead of print]134(9):
    Control of multiciliogenesis by miR-34/449 in the male reproductive tract through enforcing cell cycle exit.
    Yu-Jie Wu, Yue Liu, Yan-Qin Hu, Li Wang, Fu-Rong Bai, Chen Xu, Jing-Wen Wu.
      Multiciliated cells (MCCs) are terminally differentiated postmitotic cells that possess hundreds of motile cilia on their apical surface. Defects in cilia formation are associated with ciliopathies that affect many organs. In this study, we tested the role and mechanism of the miR-34/449 family in the regulation of multiciliogenesis in EDs using an miR-34b/c-/-; miR-449-/- double knockout (dKO) mouse model. MiR-34b/c and miR-449 depletion led to a reduced number of MCCs and abnormal cilia structure in the EDs starting from postnatal day (P)14. However, abnormal MCC differentiation in the dKO EDs could be observed as early as P7. RNA-seq analyses revealed that the aberrant development of MCCs in the EDs of dKO mice was associated with the upregulation of genes involved in cell cycle control. Using a cyclin-dependent kinase inhibitor to force cell cycle exit promoted MCC differentiation, and partially rescued the defective multiciliogenesis in the EDs of dKO mice. Taken together, our results suggest that miR-34b/c and miR-449 play an essential role in multiciliogenesis in EDs by regulating cell cycle exit.
    Keywords:  Cell cycle; Male reproductive tract; Motile cilia; Multiciliogenesis; miR-34/449
    DOI:  https://doi.org/10.1242/jcs.253450
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