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Pathogenesis: Molecular mechanisms of osteoporosis
Published in Peter V. Giannoudis, Thomas A. Einhorn, Surgical and Medical Treatment of Osteoporosis, 2020
Anastasia E. Markatseli, Theodora E. Markatseli, Alexandros A. Drosos
Wnt proteins can activate three intracellular signaling pathways: (a) the planar cell polarity pathway, which plays a dominant role in embryogenesis; (b) the Wnt/Cα2+ pathway, which regulates cell migration; and (c) the canonical Wnt signaling pathway, which is involved in the bone remodeling as well as in the development and differentiation of organs in mammals (223,231–233). The canonical Wnt signaling pathway seems to play a crucial role in both osteoblast precursors and differentiated osteoblasts (227,234–238).
Wnt signaling in spermatogenesis and male infertility
Published in Rajender Singh, Molecular Signaling in Spermatogenesis and Male Infertility, 2019
Vertika Singh, Meghali Joshi, Kiran Singh, Rajender Singh
Results from several studies have provided contradictory evidence regarding the effect of Wnt/β signaling on the Sertoli cells. The deletion of β-catenin did not show any observable effects on Sertoli cells; however, the stabilization of β-catenin is associated with immature, incompletely differentiated Sertoli cells. Its stabilization also results in reduced proliferation and increased apoptosis of germ cells (4). APC knockout mice with truncated APC protein show impairment of Sertoli and germ cell conjunction via the activation of the Wnt/β-catenin pathway. This highlights the effect of Wnt/β-catenin inhibition on the maturation and proliferation of Sertoli cells. Similarly, Dkk3 (63) mutants also show Sertoli cell defects via Wnt/β-catenin pathway inhibition. Apart from the canonical Wnt signaling molecules, Wnt signaling ligands such as Wnt4 and Wnt11 also regulate Sertoli cell polarity via a noncanonical planar cell polarity (PCP) pathway.
Approaches to Studying Polycystic Kidney Disease in Zebrafish
Published in Jinghua Hu, Yong Yu, Polycystic Kidney Disease, 2019
Defects in the cell polarity and cell migration are closely associated with PKD in both zebrafish and mammals. Cell polarity refers to both apical-basal polarity and planar cell polarity. Similar to other epithelial cells, renal epithelial cells have established apical-basolateral polarity with the apical side facing the lumen and basolateral connecting to the neighboring cells or cellular matrix. In both mice and zebrafish, defects in apical-basolateral polarity have been discovered in several PKD models, for example, ADPKD, JBTS (Figure 12.2c).14,32,33 Meanwhile, disruption of proteins required for apical-basolateral polarity (e.g., Dlg5, Scribble, Crumbs) in both mice and zebrafish also leads to PKD.34–36
Renal ciliopathies: promising drug targets and prospects for clinical trials
Published in Expert Opinion on Therapeutic Targets, 2023
Laura Devlin, Praveen Dhondurao Sudhindar, John A. Sayer
The primary cilium acts a vital transducer in numerous signaling pathways. Patched 1 (PTCH1), the Sonic hedgehog (Shh) receptor, localizes to the ciliary membrane and prevents entry of Smoothened (SMO) [16]. Upon Shh binding to PTCH1, PTCH1 is trafficked out of the cilium allowing SMO to accumulate in the primary cilium, which activates Gli transcription factors. Shh signaling pathway is vital in processes such as cell determination and patterning, and is involved in proper kidney development and functioning, with defective signaling implicated in various renal ciliopathies [16–19]. Components of the canonical Wnt signaling pathway, which is involved in cell proliferation, differentiation and survival, are located at the primary cilium [20]. Components of the non-canonical Wnt planar cell polarity pathway (PCP), regulating cell morphology, migration, and orientated cell division, are also present at the primary cilium [20]. PCP signaling is required for proper nephron tubular formation and maintenance, defects of which can lead to cystogenesis within the kidney tubules [18,21,22]. There are other ciliary signaling pathways which are vital in cell cycle regulation and proliferation, that have been implicated in proper renal tubular formation and kidney function. These includes cyclic AMP (cAMP) signaling, mammalian target of rapamycin (mTOR) signaling, epidermal growth factor (EGF) signaling, AMP-activated protein kinase (AMPK) signaling and insulin-like growth factor (IGF) signaling, although this list is not exhaustive [23,24].
Abnormal larval neuromuscular junction morphology and physiology in Drosophila prickle isoform mutants with known axonal transport defects and adult seizure behavior
Published in Journal of Neurogenetics, 2022
Atsushi Ueda, Tristan C. D. G. O’Harrow, Xiaomin Xing, Salleh Ehaideb, J. Robert Manak, Chun-Fang Wu
Mutations of the Drosophila planar cell polarity (PCP) gene prickle (pk) alter cuticular bristles and ommatidia organization (Gubb & García-Bellido, 1982; Tree et al., 2002). Two Pk protein isoforms Pkpk and Pksple are expressed post-embryonically and disruption of either isoform leads to different aspects of bristle defects (Gubb et al., 1999). Notably, the pk gene is conserved across humans, mice, zebrafish, and Drosophila, and has been linked to epileptic behaviors in all these organisms (Tao et al., 2011). Adult pksple/+, but not pkpk/+, flies (pksple and pkpk heretofore referred to as sple and pk, respectively) show ataxia, hypersensitivity to mechanical shock (bang sensitivity), and a myoclonic-like seizure phenotype, mirroring the epilepsy syndrome observed in human patients with PRICKLE gene mutations (Ehaideb et al., 2014, 2016). Additionally, in larval motor axons, defective microtubule dynamics and vesicular transport have been reported in an isoform-specific fashion (Ehaideb et al., 2014). In pk/+ mutant larvae, axonal vesicular transport is decreased while sple/+ larvae show enhanced anterograde vesicle transport. Furthermore, the sple/+ epileptic phenotypes can be rescued by a mutation of the motor protein subunit Kinesin light chain (Klc), suggesting an association of epileptic phenotypes to neuronal microtubule-mediated transport (Ehaideb et al., 2014).
The biochemistry, signalling and disease relevance of RYK and other WNT-binding receptor tyrosine kinases
Published in Growth Factors, 2018
James P. Roy, Michael M. Halford, Steven A. Stacker
WNT signalling is commonly segregated into β-catenin-dependent (also referred to as canonical) versus β-catenin-independent, or non-canonical, pathways. The canonical pathway results in the stabilization and nuclear localization of β-catenin. A transcription factor complex formed of β-catenin and T cell factor (TCF)/lymphoid enhancer factor (LEF) family members passes into the nucleus driving the transcription of WNT target genes (Clevers & Nusse, 2012). In contrast, there are multiple non-canonical WNT-signalling pathways; the planar cell polarity (PCP) and WNT/Ca2+ pathways being the best characterized (Niehrs, 2012). The identity of WNT receptor/co-receptor signalling complexes formed in the membrane is a major factor influencing context-dependent pathway regulation and resulting cellular responses (Niehrs, 2012; van Amerongen & Nusse, 2009). While some aspects of the signal transduction pathways arising from WNT activation of RYK have been described (Figure 2), their context-dependency and the physiological relevance are still poorly understood.