WNT5A is transported via lipoprotein particles in the cerebrospinal fluid to regulate hindbrain morphogenesis

Kaiser, Karol; Gyllborg, Daniel; Procházka, Jan; Salašová, Alena; Kompaníková, Petra; Molina, Francisco Lamus; Laguna‐Goya, Rocío; Radaszkiewicz, Tomasz; Harnoš, Jakub; Procházková, Michaela; Potěšil, David; Barker, Roger A.; Gato, Á.; Zdráhal, Zbyněk; Sedláček, Radislav; Arenas, Ernest; Villaescusa, J. Carlos; Bryja, Vı́tězslav

doi:10.1038/s41467-019-09298-4

Cited by 70 publications

(75 citation statements)

References 68 publications

(47 reference statements)

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“…[24][25][26] Wnts may bind to lipoproteins that stabilize them as well. 19,27 Interestingly, macrophage-derived EVs carry Wnt proteins to ISCs in intestinal repair, 11 and we provide evidence that fibroblast-derived EVs transfer Wnt activity in the ISC niche in WT organoids as well. Importantly, we found no rescue effect with EVs when R-Spondin1 lacked from the culture medium.…”

Section: Discussionmentioning

confidence: 69%

Extracellular vesicles transmit epithelial growth factor activity in the intestinal stem cell niche

et al. 2019

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Extracellular vesicles (EV) are membrane-surrounded vesicles that represent a novel way of intercellular communication by carrying biologically important molecules in a concentrated and protected form. The intestinal epithelium is continuously renewed by a small proliferating intestinal stem cell (ISC) population, residing at the bottom of the intestinal crypts in a specific microenvironment, the stem cell niche. By using 3D mouse and human intestinal organoids, we show that intestinal fibroblast-derived EVs are involved in forming the ISC niche by transmitting Wnt and epidermal growth factor (EGF) activity. With a mouse model that expresses EGFP in the Lgr5+ ISCs, we prove that loss in ISC number in the absence of EGF is prevented by fibroblastderived EVs. Furthermore, we demonstrate that intestinal fibroblast-derived EVs carry EGF family members, such as amphiregulin. Mechanistically, blocking EV-bound amphiregulin inhibited the EV-induced survival of organoids. In contrast, EVs have no role in transporting R-Spondin, a critical niche factor amplifying Wnt signaling. Collectively, we prove the important role of fibroblast-derived EVs as a novel transmission mechanism of factors in the normal ISC niche. K E Y W O R D S amphiregulin, exosomes, extracellular vesicle, fibroblast, intestinal stem cell, Lgr5, organoid, Wnt

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Section: Discussionmentioning

confidence: 69%

Extracellular vesicles transmit epithelial growth factor activity in the intestinal stem cell niche

et al. 2019

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“…Furthermore, Wnt5a is produced in the murine choroid plexus (CP) and is required for morphogenesis of the dorsal hindbrain. Recently, it was shown that Wnt5a colocalises with lipoproteins in CP epithelial cells and target hindbrain progenitors at the ventricle, which express Wnt signalling components as well as receptors for lipoprotein particles (Kaiser et al, 2019). Although a mechanism explaining how Wnt may be loaded onto lipoproteins is yet to be determined, lipoprotein-mediated transport seems to be an important Wnt transport mechanism in the context of the cerebrospinal fluid.…”

Section: Lipoproteinsmentioning

confidence: 99%

Mechanisms of intercellular Wnt transport

2019

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Wnt proteins are secreted glycoproteins that regulate multiple processes crucial to the development and tissue homeostasis of multicellular organisms, including tissue patterning, proliferation, cell fate specification, cell polarity and migration. To elicit these effects, Wnts act as autocrine as well as paracrine signalling molecules between Wnt-producing and Wnt-receiving cells. More than 40 years after the discovery of the Wg/Wnt pathway, it is still unclear how they are transported to fulfil their paracrine signalling functions. Several mechanisms have been proposed to mediate intercellular Wnt transport, including Wnt-binding proteins, lipoproteins, exosomes and cytonemes. In this Review, we describe the evidence for each proposed mechanism, and discuss how they may contribute to Wnt dispersal in tissue-specific and context-dependent manners, to regulate embryonic development precisely and maintain the internal steady state within a defined tissue.

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“…It has recently emerged that the cerebrospinal fluid (CSF) contains many signals important for cell differentiation, and is an important route for the control of morphogenesis ( Fame and Lehtinen, 2020 ). The CSF is a complex liquid filling the central nervous system cavities containing a set of diffusible signaling cues guiding neurogenesis ( Lehtinen et al, 2011 ) and brain morphology in a tissue autonomous manner ( Kaiser et al, 2019 ; Langford et al, 2020 ). The CSF circulation is in part generated by the coordinated movement of cilia projecting to the lumen of brain ventricles and central canal of the spinal cord ( Faubel et al, 2016 ; Hagenlocher et al, 2013 ; Olstad et al, 2019 ; Sternberg et al, 2018 ; Thouvenin et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Adrenergic activation modulates the signal from the Reissner fiber to cerebrospinal fluid-contacting neurons during development

Cantaut-Belarif

Orts-Del’Immagine

Penru

et al. 2020

eLife

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The cerebrospinal fluid (CSF) contains an extracellular thread conserved in vertebrates, the Reissner fiber, which controls body axis morphogenesis in the zebrafish embryo. Yet, the signaling cascade originating from this fiber to ensure body axis straightening is not understood. Here, we explore the functional link between the Reissner fiber and undifferentiated spinal neurons contacting the CSF (CSF-cNs). First, we show that the Reissner fiber is required in vivo for the expression of urp2, a neuropeptide expressed in CSF-cNs. We show that the Reissner fiber is also required for embryonic calcium transients in these spinal neurons. Finally, we study how local adrenergic activation can substitute for the Reissner fiber-signaling pathway to CSF-cNs and rescue body axis morphogenesis. Our results show that the Reissner fiber acts on CSF-cNs and thereby contributes to establish body axis morphogenesis, and suggest it does so by controlling the availability of a chemical signal in the CSF.

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WNT5A is transported via lipoprotein particles in the cerebrospinal fluid to regulate hindbrain morphogenesis

Cited by 70 publications

References 68 publications

Extracellular vesicles transmit epithelial growth factor activity in the intestinal stem cell niche

Extracellular vesicles transmit epithelial growth factor activity in the intestinal stem cell niche

Mechanisms of intercellular Wnt transport

Adrenergic activation modulates the signal from the Reissner fiber to cerebrospinal fluid-contacting neurons during development

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