CD44 regulates dendrite morphogenesis through Src tyrosine kinase-dependent positioning of the Golgi apparatus

Skupien, Anna; Konopka, Anna; Trzaskoma, Paweł; Labus, Josephine; Gorlewicz, Adam; Swiech, Lukasz; Babraj, Matylda; Dolezyczek, Hubert; Figiel, Izabela; Ponimaskin, Evgeni; Włodarczyk, Jakub; Jaworski, Jacek; Wilczyński, Grzegorz M.; Dzwonek, Joanna

doi:10.1242/jcs.154542

Cited by 44 publications

(34 citation statements)

References 75 publications

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“…E11 binds to CD44, a molecule also expressed in neuronal dendrites, 25 and expression of either molecule has been associated with osteocytic dendrite branching. 26, 27 Osteocytic dendrites also contain α-actinin and fimbrin, actin-bundling proteins required for the cytoskeletal organization of osteocytes isolated from chicken.…”

Section: Molecular and Functional Signature Of Osteocytesmentioning

confidence: 99%

Osteocytic signalling pathways as therapeutic targets for bone fragility

2016

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Osteocytes are differentiated osteoblasts that become surrounded by matrix during the process of bone formation. The acquisition of the osteocyte phenotype is achieved by profound modifications in gene expression that confer adaptation to the changing cellular functions and constitute the molecular signature of osteocytes. The levels of expression of genes characteristic of osteoblasts is altered; and the expression of genes/proteins that impart dendritic cellular morphology, regulate matrix mineralization, and control the function of bone surface cells, is orderly modulated during osteocytogenesis. The discovery of human mutations of osteocytic genes had contributed to a large extent to reveal the role of osteocytes in bone homeostasis. Osteocytes are targets of mechanical force imposed to the skeleton and also play a critical role in integrating mechanosensory pathways with the action of hormones, thereby leading to the orchestrated response of bone to environmental cues. Current, novel therapeutic approaches harness this accumulating knowledge by targeting osteocytic signaling pathways and messengers to improve skeletal health.

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Section: Molecular and Functional Signature Of Osteocytesmentioning

confidence: 99%

Osteocytic signalling pathways as therapeutic targets for bone fragility

2016

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“…However, growth of dorsal root ganglion neurons on a hyaluronan substrate reduces neurite extension49. Further, the major hyaluronan receptor CD44 is expressed on neuronal dendrites, and blockade of CD44 increases dendritic arborisation of cortical and hippocampal neurons both in vitro and in vivo 50. Conversely, blockade of RHAMM, another hyaluronan receptor, inhibits neurite extension in cultures of primary neurons and other neural cell lines51.…”

Section: Discussionmentioning

confidence: 99%

Hyaluronan synthesis by developing cortical neurons in vitro

Fowke

Karunasinghe

Bai

et al. 2017

Sci Rep

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Hyaluronan is a linear glycosaminoglycan that forms the backbone of perineuronal nets around neurons in the cerebral cortex. However, it remains controversial whether neurons are capable of independent hyaluronan synthesis. Herein, we examined the expression of hyaluronan and hyaluronan synthases (HASs) throughout cortical neuron development in vitro. Enriched cultures of cortical neurons were established from E16 rats. Neurons were collected at days in vitro (DIV) 0 (4 h), 1, 3, 7, 14, and 21 for qPCR or immunocytochemistry. In the relative absence of glia, neurons exhibited HAS1–3 mRNA at all time-points. By immunocytochemistry, puncta of HAS2–3 protein and hyaluronan were located on neuronal cell bodies, neurites, and lamellipodia/growth cones from as early as 4 h in culture. As neurons matured, hyaluronan was also detected on dendrites, filopodia, and axons, and around synapses. Percentages of hyaluronan-positive neurons increased with culture time to ~93% by DIV21, while only half of neurons at DIV21 expressed the perineuronal net marker Wisteria floribunda agglutinin. These data clearly demonstrate that neurons in vitro can independently synthesise hyaluronan throughout all maturational stages, and that hyaluronan production is not limited to neurons expressing perineuronal nets. The specific structural localisation of hyaluronan suggests potential roles in neuronal development and function.

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“…All three intracellular messengers that we evaluated, PKA, PKC and Src, have also been associated to CD44 receptor signaling (Lee et al, 2008; Bourguignon et al, 2009; Bourguignon et al, 2010; Campo et al, 2010; Zhang et al, 2014). Although it has not been established how CD44 interacts with PKA, it has been shown that CD44 can directly activate PKC (Bourguignon et al, 2009; Campo et al, 2010), and members of the Src family kinases are considered crucial for CD44 signaling (Ponta et al, 2003; Skupien et al, 2014; Dzwonek and Wilczynski, 2015). To directly activate the CD44 receptor we used the peptide A6 (Piotrowicz et al, 2011; Finlayson, 2015); its administration produced robust hyperalgesia that was inhibited by both the CD44 antagonist A5G27 and HMWH, confirming the action of A6 on the CD44 receptor.…”

Section: Discussionmentioning

confidence: 99%

Extracellular matrix hyaluronan signals via its CD44 receptor in the increased responsiveness to mechanical stimulation

et al. 2016

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We propose that the extracellular matrix signals CD44, a hyaluronan receptor, to increase the responsiveness to mechanical stimulation. We report that intradermal injection of hyaluronidase induces mechanical hyperalgesia, that is inhibited by co-administration of a CD44 receptor antagonist, A5G27. The intradermal injection of low (LMWH) but not high (HMWH) molecular weight hyaluronan also induces mechanical hyperalgesia, an effect that was attenuated by the pretreatment with HMWH or A5G27. Pretreatment with HMWH also attenuated the hyperalgesia induced by hyaluronidase. Similarly, intradermal injection of A6, a CD44 receptor agonist, produced hyperalgesia that was inhibited by HMWH and A5G27. Inhibitors of protein kinase A and Src, but not protein kinase C, significantly attenuated the hyperalgesia induced by both A6 and LMWH. Finally, to determine if CD44 receptor signaling is involved in a preclinical model of inflammatory pain, we evaluated the effect of A5G27 and HMWH on the mechanical hyperalgesia associated with the inflammation induced by carrageenan. Both A5G27 and HMWH attenuated carrageenan-induced mechanical hyperalgesia. Thus, while LMWH acts at its cognate receptor, CD44, to induce mechanical hyperalgesia, HMWH acts at the same receptor as an antagonist. That the local administration of HMWH or A5G27 inhibits carrageenan-induced hyperalgesia supports the suggestion that carrageenan produces changes in the extracellular matrix that contributes to inflammatory pain. These studies define a clinically relevant role for signaling by the hyaluronan receptor, CD44, in increased responsiveness to mechanical stimulation.

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CD44 regulates dendrite morphogenesis through Src tyrosine kinase-dependent positioning of the Golgi apparatus

Cited by 44 publications

References 75 publications

Osteocytic signalling pathways as therapeutic targets for bone fragility

Osteocytic signalling pathways as therapeutic targets for bone fragility

Hyaluronan synthesis by developing cortical neurons in vitro

Extracellular matrix hyaluronan signals via its CD44 receptor in the increased responsiveness to mechanical stimulation

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